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 imped 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 . An intranasal device for administration of a pharmaceutical composition comprising:
a reservoir containing a dose of the pharmaceutical composition; and
a delivery head defining a delivery aperture;
wherein the pharmaceutical composition is a dry powder comprising:
epinephrine or a pharmaceutically acceptable salt thereof, wherein the dose contains between about 3.5 mg and about 5.5 mg of the epinephrine or the pharmaceutically acceptable salt thereof, and
a carrier;
wherein the intranasal device is configured to deliver the dose of the pharmaceutical composition into a body via the delivery aperture to produce at least one of:
(A) a relative mean maximum epinephrine plasma concentration after the dose is delivered into the body (Cmax) that is greater than a Cmax of a first reference dose and less than a Cmax of a second reference dose, or
(B) a time to reach a maximum epinephrine plasma concentration (Tmax) that is greater than a Tmax of the first reference dose and less than a Tmax of the second reference dose; and
wherein the first reference dose contains about 0.3 mg of epinephrine or a pharmaceutically acceptable salt that is delivered intramuscularly via a manual injection, and the second reference dose contains about 0.3 mg of epinephrine or a pharmaceutically acceptable salt that is delivered intramuscularly via an autoinjector.
2 . The intranasal device of claim 1 , wherein the pharmaceutical composition is formulated such that delivery of the dose of the pharmaceutical composition via the delivery aperture produces a spray having an emitted particle size distribution characterized by a Dv50 of between about 25 microns and about 200 microns.
3 . The intranasal device of claim 1 , wherein the pharmaceutical composition has a moisture content of between about 3% and 6%.
4 . The intranasal device of claim 1 , wherein a baseline-corrected epinephrine concentration present in the body is at least 100 pg/mL after about 5 minutes after delivery of the dose.
5 . The intranasal device of claim 1 , wherein a quantity of the pharmaceutical composition is between about 10.0 mg and about 40.0 mg.
6 . The intranasal device of claim 1 , wherein the carrier includes any of mannitol, a cyclodextrin, citric acid, lactose, or sodium carboxymethylcellulose.
7 . The intranasal device of claim 1 , wherein the carrier includes lactose monohydrate.
8 . The intranasal device of claim 1 , wherein the pharmaceutical composition does not include an alpha-adrenergic blocker.
9 . An intranasal device for administration of a pharmaceutical composition comprising:
a reservoir containing a dose of the pharmaceutical composition;
wherein the pharmaceutical composition is a dry powder comprising:
epinephrine or a pharmaceutically acceptable salt thereof, wherein the dose contains between about 3.5 mg and about 5.5 mg of the epinephrine or the pharmaceutically acceptable salt thereof,
wherein the intranasal device is configured to deliver the dose of the pharmaceutical composition into a body via a delivery aperture to produce at least one of:
(A) a relative mean maximum epinephrine plasma concentration after the dose is delivered into the body (Cmax) that is greater than a Cmax of a first reference dose and less than a Cmax of a second reference dose, or
(B) a time to reach a maximum epinephrine plasma concentration (Tmax) that is greater than a Tmax of the first reference dose and less than a Tmax of the second reference dose; and
wherein the first reference dose contains about 0.3 mg of epinephrine or a pharmaceutically acceptable salt that is delivered intramuscularly via a manual injection, and the second reference dose contains about 0.3 mg of epinephrine or a pharmaceutically acceptable salt that is delivered intramuscularly via an autoinjector.
10 . The intranasal device of claim 9 , wherein the pharmaceutical composition is formulated such that delivery of the dose of the pharmaceutical composition via the delivery aperture produces a spray having an emitted particle size distribution characterized by a Dv50 of between about 25 microns and about 200 microns.
11 . The intranasal device of claim 9 , wherein the pharmaceutical composition has a moisture content of between about 3% and about 6%.
12 . The intranasal device of claim 9 , wherein a baseline-corrected epinephrine concentration present in the body is at least 100 pg/mL after about 5 minutes after delivery of the dose.
13 . The intranasal device of claim 9 , wherein a quantity of the pharmaceutical composition is between about 10.0 mg and about 40.0 mg.
14 . The intranasal device of claim 9 , wherein the pharmaceutical composition further comprises a carrier, wherein the carrier includes any of mannitol, a cyclodextrin, citric acid, lactose, or sodium carboxymethylcellulose.
15 . The intranasal device of claim 14 , wherein the carrier includes lactose monohydrate.
16 . The intranasal device of claim 9 , wherein the pharmaceutical composition does not include an alpha-adrenergic blocker.
17 . A dry powder pharmaceutical composition, comprising:
epinephrine or a pharmaceutically acceptable salt thereof;
wherein a dose of the dry powder pharmaceutical composition contains about 3.5 mg to about 5.5 mg of the epinephrine or the pharmaceutically acceptable salt thereof; and
wherein a dose of the dry powder pharmaceutical composition results in at least one of:
(A) a relative mean maximum epinephrine plasma concentration after the dose is delivered into the body (Cmax) is greater than a Cmax of a first reference dose and less than a Cmax of a second reference dose, or
(B) a time to reach a maximum epinephrine plasma concentration (Tmax) is greater than a Tmax of the first reference dose and less than a Tmax of the second reference dose;
wherein the first reference dose contains about 0.3 mg of epinephrine or a pharmaceutically acceptable salt that is delivered intramuscularly via a manual injection and the second reference dose contains about 0.3 mg of epinephrine or a pharmaceutically acceptable salt that is delivered intramuscularly via an autoinjector.
18 . The dry powder pharmaceutical composition of claim 17 , wherein the dry powder pharmaceutical composition does not include an alpha-adrenergic blocker.
19 . The dry powder pharmaceutical composition of claim 17 , wherein the dry powder pharmaceutical composition is formulated such that delivery of the dose of the dry powder pharmaceutical composition produces a dry powder spray having an emitted particle size distribution characterized by a Dv50 of between about 25 microns and about 200 microns.
20 . The dry powder pharmaceutical composition of claim 17 , wherein the dry powder pharmaceutical composition further comprises a carrier.