COMPOSITIONS, DEVICES, AND METHODS FOR INTRANASAL DELIVERY OF DRY POWDER EPINEPHRINE
Intranasal dry powder epinephrine compositions are described herein. The compositions include epinephrine or a pharmaceutically acceptable salt thereof, as well as a stabilizing agent and a carrier. The stabilizing agent is operable to include citric acid, or a pharmaceutically acceptable salt derived therefrom. Such intranasal compositions as described herein are useful in the treatment of health conditions which threaten the central nervous system (CNS) and impede the actions of alpha and beta-adrenergic receptors. Such health conditions include anaphylaxis, bronchospasms, respiratory impairment, organophosphate poisoning, and major adverse cardiac events (MACE).
1 . A method for intranasal administration of a dry powder pharmaceutical composition comprising:
intranasally administering to a human a single dose of a dry powder pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof;
wherein the single dose of the dry powder pharmaceutical composition contains about 3.5 mg to about 5.5 mg of epinephrine or a pharmaceutically acceptable salt thereof; and
wherein the intranasal administration of the single dose produces an increase in systolic blood pressure by at least 10 mm Hg for a duration of up to 50 minutes after administration of the single dose, an increased heart rate of at least 10 beats per minute for a duration of up to 50 minutes after administration of the single dose, and an increased diastolic blood pressure by at least 10 mm Hg for a duration of up to 50 minutes after administration of the single dose.
2 . The method of claim 1 , wherein a mean baseline-corrected epinephrine concentration present in the human is at least 100 μg/mL after between about 5 minutes to about 15 minutes after delivery of the single dose.
3 . The method of claim 1 , wherein the intranasal administration of the single dose produces plasma epinephrine concentrations in the human with the time to reach the maximum epinephrine plasma concentration (Tmax) between about 18 minutes and about 28 minutes.
4 . The method of claim 1 , wherein the dry powder pharmaceutical composition does not include an alpha-adrenergic blocker.
5 . The method of claim 1 , wherein the dry powder pharmaceutical composition is formulated such that delivery of the single dose of the dry powder pharmaceutical composition produces a spray having an emitted particle size distribution characterized by a Dv50 of between 25 microns and 200 microns.
6 . The method of claim 1 , wherein the dry powder pharmaceutical composition further comprises a carrier, wherein the carrier is lactose.
7 . The method of claim 1 , wherein no dose response occurs for the about 3.5 mg dose and the about 5.5 mg dose of epinephrine or a pharmaceutically acceptable salt thereof for heart rate, systolic blood pressure, or diastolic blood pressure.
8 . The method of claim 1 , wherein the dry powder pharmaceutical composition has a moisture content of between 3% w/w and 6% w/w.
9 . A method for intranasal administration of a pharmaceutical composition comprising:
intranasally administering to a human a single dose of a dry powder pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof and a carrier;
wherein the single dose of the dry powder pharmaceutical composition contains about 3.5 mg to about 5.5 mg of epinephrine or a pharmaceutically acceptable salt thereof; and
wherein the intranasal administration of the single dose produces an increase in systolic blood pressure by at least 10 mm Hg for a duration of up to 50 minutes after administration of the single dose, an increased heart rate of at least 10 beats per minute for a duration of up to 50 minutes after administration of the single dose, and an increased diastolic blood pressure by at least 10 mm Hg for a duration of up to 50 minutes after administration of the single dose.
10 . The method of claim 9 , wherein a mean baseline-corrected epinephrine concentration present in the human is at least 100 μg/mL after between about 5 minutes to about 15 minutes after delivery of the single dose.
11 . The method of claim 9 , wherein the intranasal administration of the single dose produces plasma epinephrine concentrations in the human with the time to reach the maximum epinephrine plasma concentration (Tmax) between about 18 minutes and about 28 minutes.
12 . The method of claim 9 , wherein the dry powder pharmaceutical composition does not include an alpha-adrenergic blocker.
13 . The method of claim 9 , wherein the dry powder pharmaceutical composition is formulated such that delivery of the dose of the dry powder pharmaceutical composition produces a spray having an emitted particle size distribution characterized by a Dv50 of between 25 microns and 200 microns.
14 . The method of claim 9 , wherein the carrier is lactose.
15 . A dry powder pharmaceutical composition comprising:
epinephrine or a pharmaceutically acceptable salt thereof; and
a carrier;
wherein a single dose of the dry powder pharmaceutical composition contains about 3.5 mg to about 5.5 mg of epinephrine or the pharmaceutically acceptable salt thereof; and
wherein a single dose of the dry powder pharmaceutical composition produces an increase in systolic blood pressure by at least 10 mm Hg for a duration of up to 50 minutes after administration of the single dose, an increased heart rate of at least 10 beats per minute for a duration of up to 50 minutes after administration of the single dose, and an increased diastolic blood pressure by at least 10 mm Hg for a duration of up to 50 minutes after administration of the single dose.
16 . The dry powder pharmaceutical composition of claim 15 , wherein the dry powder pharmaceutical composition does not include an alpha-adrenergic blocker.
17 . The dry powder pharmaceutical composition of claim 15 , wherein the dry powder pharmaceutical composition is formulated such that delivery of the dose of the dry powder pharmaceutical composition produces a spray having an emitted particle size distribution characterized by a Dv50 of between 25 microns and 200 microns.
18 . The dry powder pharmaceutical composition of claim 15 , wherein the dry powder pharmaceutical composition has a moisture content of between 3% w/w and 6% w/w.
19 . The dry powder pharmaceutical composition of claim 15 , wherein the carrier is lactose.
20 . The dry powder pharmaceutical composition of claim 15 , wherein no dose response occurs for the about 3.5 mg dose and the about 5.5 mg dose of epinephrine or a pharmaceutically acceptable salt thereof for heart rate, systolic blood pressure, or diastolic blood pressure.