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 (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. 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.

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 effective dose is administered by an 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 effective dose is (i) no more than 2.0 mg DHE or salt thereof, (ii) less than 2.0 mg DHE or salt thereof, (iii) 1.2-1.8 mg DHE or salt thereof, (iv) 1.4-1.6 mg DHE or salt thereof, or (v) about 1.45 mg DHE or salt thereof. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the effective dose is administered (i) as a plurality of divided doses or (ii) as two divided doses, optionally wherein each of the divided doses is administered to each nostril. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 7 , wherein the effective dose is administered (i) over no more than 1 minute, (ii) over no more than 45 seconds, or (iii) over no more than 30 seconds. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 7 , wherein the volume of liquid composition administered per divided dose is (i) 140-250 μL, (ii) 175 μL-225 μL, or (iii) about 200 μL. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the liquid composition comprises a salt of DHE. 
     
     
         17 . The method of  claim 16 , wherein the liquid composition comprises DHE mesylate at a concentration of 2.5-7.5 mg/ml, 3.5-6.5 mg/ml or 4.0 mg/ml. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the liquid composition further comprises caffeine, optionally caffeine at a concentration of 10 mg/ml. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the liquid composition further comprises dextrose, optionally dextrose at a concentration of 50 mg/ml. 
     
     
         24 . (canceled) 
     
     
         25 . 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. 
     
     
         26 . The method of  claim 1 , wherein, following administration of the effective dose, the mean C max  of DHE is at least 1000 pg/ml, or at least 1200 pg/ml. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein,
 following administration of the effective dose, the mean plasma AUC 0-inf  of DHE is at least 3000 pg*hr/ml, at least 4000 pg*hr/ml, at least 5000 pg*hr/ml, or at least 6000 pg*hr/ml.   
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein, following administration of the effective dose, the mean peak plasma concentration (C max ) of 8′-OH-DHE is at least 50 pg/ml or at least 55 pg/ml. 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein, following administration of the effective dose, the mean plasma AUC 0-inf  of 8′-OH-DHE is at least 1000 pg*hr/ml. 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 1 , wherein the subject has (i) migraine headache with aura, (ii) migraine headache without aura, (iii) onset of at least one prodromal symptom of migraine, (iv) menstrual-associated migraine, or (v) migraine that does not respond to triptan drugs. 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 1 , wherein the subject self-administers the liquid pharmaceutical composition or a care-giver of the subject administers the liquid pharmaceutical composition to the subject. 
     
     
         52 . In a method of acutely treating migraine headache with or without aura by intranasal administration of dihydroergotamine (DHE) or salt thereof, the improvement comprising:
 administering a dose of a liquid pharmaceutical composition comprising dihydroergotamine (DHE) or salt thereof by an 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.   
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . 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. 
   
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . (canceled) 
     
     
         70 . (canceled) 
     
     
         71 . A device for delivering an intranasal dosage form comprising:
 a housing that is configured to be held by a user, the housing comprising an upper portion and an actuator grip configured to move relative to the upper portion of the housing when a force is applied to the actuator grip by the user;   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 intranasal dosage form 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.   
     
     
         72 . The device of  claim 71 , 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 a vial containing the intranasal dosage form, and a third branch configured to couple to the nozzle, optionally 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. 
     
     
         73 . (canceled) 
     
     
         74 . The device of  claim 72 , 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. 
     
     
         75 . The device of  claim 74 , wherein the force threshold to actuate the canister is greater than a force threshold to actuate a dose pump of a 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. 
     
     
         76 . The device of  claim 75 , wherein the actuator grip comprises a guiding feature that is configured to envelop at least a portion of the canister, optionally 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. 
     
     
         77 . (canceled) 
     
     
         78 . The device of  claim 76 , 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. 
     
     
         79 . (canceled) 
     
     
         80 . The device of  claim 71 , further comprising a diffuser positioned at a first end of the dose chamber such that the released propellant is configured to pass through the diffuser, optionally wherein the diffuser is configured to convert liquid propellant into gaseous propellant as the released propellant passes through the diffuser. 
     
     
         81 . (canceled) 
     
     
         82 . (canceled) 
     
     
         83 . The device of  claim 71 , wherein the dose chamber is further configured to sequentially receive the intranasal dosage form followed by the propellant. 
     
     
         84 . (canceled)