Intranasal composition of pharmaceutical countermeasures for chemical warfare nerve agents and accidental exposure to organophosphate pesticides
Inventors
Bleske, Barry • Lanpher, Ted William
Assignees
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Publication Number
US-12102629-B1
Publication Date
2024-10-01
Expiration Date
Abstract
Nasally targeted dry powder compositions and methods for their use in the treatment of exposure to organophosphate compounds including chemical warfare agents and pesticides. Compositions include anticholinergic agents and cholinesterase reactivator agents used for primary treatment and vasoactive agents and benzodiazepines used for secondary treatment of exposure, and combinations of these agents. Compositions incorporate excipients and enabling agents such as permeation enhancers, and optimal sizing of active pharmaceutical ingredient particle size to improve drug delivery across the nasal mucosa, stability, and resistance to heat degradation. Packaging and configuration of devices for dry powder nasal compositions enable their use by non-medical personnel in civilian mass casualty or battlefield environments.
Core Innovation
The invention relates to intranasal dry-powder pharmaceutical countermeasures for organophosphate exposure, including chemical warfare nerve agents and pesticides that cause acetylcholinesterase inhibition and acetylcholine excess. The compositions are configured for intranasal delivery and address respiratory failure and bronchorrhea/bronchoconstriction by combining agents acting on muscarinic receptors and nicotinic receptors and by including a cholinesterase reactivator in the formulation.
A central aspect is a combined pharmacological approach in a single intranasal dry-powder composition that includes an anti-muscarinic agent, atropine or a pharmaceutically acceptable salt thereof, together with a cholinesterase reactivator, 2-pyridine aldoxime methyl chloride or a pharmaceutically acceptable salt thereof. The composition further includes a vasodilator, phentolamine or a pharmaceutically acceptable salt thereof, and embodiments also contemplate additional secondary agents such as epinephrine and diazepam for vasoactive and anticonvulsant activity.
The document also emphasizes intranasal delivery benefits and formulation enabling agents. It describes mucoadhesives, permeation enhancers, mucosal transit reducers, carriers and excipients, and particle sizing and stability/heat resistance considerations to support nasal mucosa penetration and non-aqueous stability. Further embodiments include device and packaging features for dry powder nasal delivery, such as a dry powder nasal delivery device with replaceable nasal probes and protective secondary packaging with desiccant and optional indicator or sensing.
Claims Coverage
The independent claims identified in the provided material cover intranasal delivery devices and intranasal administration kits. Across three independent claim scopes, the main inventive features are the specified combinations of atropine and 2-pyridine aldoxime methyl chloride with additional agents such as phentolamine, epinephrine and/or diazepam, and a COMT inhibitor.
Intranasal device with atropine, 2-pyridine aldoxime methyl chloride, and phentolamine
A device for intranasal administration of a pharmaceutical composition containing atropine or a pharmaceutically acceptable salt thereof, 2-pyridine aldoxime methyl chloride or a pharmaceutically acceptable salt thereof, and phentolamine or a pharmaceutically acceptable salt thereof, with a reservoir and a means for discharging one or more doses.
Intranasal kit with first device and additional device(s)
A kit for intranasal administration including a first device with a reservoir and discharge means for a first pharmaceutical composition comprising atropine and 2-pyridine aldoxime methyl chloride, and at least one additional device with a reservoir and discharge means for at least one additional pharmaceutical composition comprising epinephrine and/or diazepam.
Intranasal device with COMT inhibitor
A device for intranasal administration of a pharmaceutical composition including atropine or a pharmaceutically acceptable salt thereof and 2-pyridine aldoxime methyl chloride or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further comprises a catechol-o-methyl transferase (COMT) inhibitor.
Across the independent claims, the coverage centers on intranasal administration devices and kits that deliver atropine and 2-pyridine aldoxime methyl chloride. Additional scope includes phentolamine, epinephrine and/or diazepam, and a COMT inhibitor, all delivered via reservoir-and-discharge devices.
Stated Advantages
Described advantages of intranasal delivery over IM/IV include no needles and non-aqueous stability.
Broader environmental usability is described for intranasal delivery.
Potentially improved CNS delivery is described for intranasal delivery.
Documented Applications
Intranasal dry-powder pharmaceutical countermeasures for organophosphate exposure, including chemical warfare nerve agents and pesticides.
Treatment/mitigation context associated with acetylcholinesterase inhibition and acetylcholine excess, including respiratory failure and bronchorrhea/bronchoconstriction.
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