Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
Inventors
Cook, Robert O. • Shrewsbury, Stephen B. • Ramadan, Nabih N. • Armer, Thomas A.
Assignees
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Publication Number
US-9833451-B2
Publication Date
2017-12-05
Expiration Date
Abstract
Pharmaceutical compositions containing dihydroergotamine (DHE) and methods in which DHE is administered to patients for treatment of migraine without side effects or adverse effects are disclosed. Methods for rapid treatment of migraine with DHE are disclosed comprising: dampening the peak plasma concentration (Cmax) and slightly delaying the peak such as to avoid activating the dopaminergic and adrenergic receptors, while achieving sufficient active binding to the serotonin receptors to provide relief from migraine symptoms within a timeframe that permits rapid resolution of migraine symptoms. Inhaler devices suitable for the methods are disclosed. Kits for practicing the methods of invention are disclosed.
Core Innovation
The invention relates to a method of rapidly treating migraine in a human by delivering dihydroergotamine mesylate such that pharmacokinetic targets are met. The method provides a mean peak plasma concentration (Cmax) of dihydroergotamine that is less than 15,000 pg/ml within a mean time to Cmax (Tmax) that is less than 20 minutes after delivery. The approach is directed to rapid relief of migraine symptoms while controlling the timing and level of dihydroergotamine exposure.
The invention further specifies that the delivering is via pulmonary administration by oral inhalation using a breath actuated pressurized metered dose inhaler (pMDI). The breath actuated pMDI contains a suspension of dihydroergotamine mesylate in a hydrofluoroalkane propellant blend. The propellant blend consists of 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea) and 1,1,1,2-tetrafluoroethane (HFA 134a), thereby defining the formulation for the inhaled pulmonary dosing.
The described rapid treatment method is characterized by delivering a total dose of between 0.1 and 10.0 mg of dihydroergotamine mesylate per migraine attack. This delivery is positioned as providing rapid relief of the migraine in the human, based on achieving the defined Cmax and Tmax relationship after pulmonary administration via the breath actuated pMDI.
Claims Coverage
The disclosed subject matter includes one independent claim directed to a rapid migraine treatment method with specific pharmacokinetic targets and a defined pulmonary breath-actuated pMDI delivery format, plus dependent claims that refine the propellant composition and narrow the dihydroergotamine mesylate dose ranges.
Rapid migraine treatment with controlled Cmax and Tmax
A method of rapidly treating migraine in a human by delivering a total dose of 0.1 to 10.0 mg of dihydroergotamine mesylate per migraine attack to provide a mean Cmax of dihydroergotamine less than 15,000 pg/ml within a mean Tmax less than 20 minutes after delivery, thereby providing rapid relief of the migraine.
Pulmonary breath actuated pMDI delivery of DHE mesylate suspension
Delivering the dihydroergotamine mesylate via pulmonary administration by oral inhalation using a breath actuated pressurized metered dose inhaler (pMDI), where the breath actuated pMDI contains a suspension of the dihydroergotamine mesylate in a hydrofluoroalkane propellant blend.
HFA 227ea/HFA 134a propellant blend for the suspension
Using a hydrofluoroalkane propellant blend consisting of 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea) and 1,1,1,2-tetrafluoroethane (HFA 134a) in the inhaler suspension.
Specific propellant ratio for the suspension
The method includes a propellant blend made from 70:30 HFA 227ea to HFA 134a.
Intermediate total DHE mesylate dose per attack
The method is carried out using a total dose of 0.5 mg to 5.0 mg per migraine attack.
Narrower total DHE mesylate dose per attack
The method is characterized by administering a total dose of 1.0 mg to 2.0 mg per migraine attack.
Overall, the claim set centers on rapid migraine treatment using dihydroergotamine mesylate delivered by oral inhalation with a breath actuated pMDI, while achieving defined pharmacokinetic criteria (mean Cmax < 15,000 pg/ml and mean Tmax < 20 minutes). Dependent refinements specify the HFA 227ea/HFA 134a composition and narrow the total dihydroergotamine mesylate dose ranges per migraine attack.
Stated Advantages
Rapid relief of the migraine in the human.
Documented Applications
Treating migraine in a human using pulmonary administration by oral inhalation with a breath actuated pressurized metered dose inhaler (pMDI).
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