# US 11,433,063 B1 · Intranasal composition of pharmaceutical countermeasures for chemical warfare nerve agents and accidental exposure to organophosphate pesticides

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- Number: US 11,433,063 B1
- Document ID: US11433063B1
- Status: Granted
- Kind: B1
- Application number: 17/687,167
- Filed: 2022-03-04
- Granted: 2022-09-06
- Earliest claimed: 2019-03-12
- Assignees: Belhaven BioPharma Inc.
- Applicants: Belhaven BioPharma Inc.
- Inventors: Barry Bleske; Ted William Lanpher
- Web page: https://patentgrep.com/patent/US11433063B1

## CPC

- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 9/0043: {Nose}
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/4425: Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61M 11/007: {Syringe-type or piston-type sprayers or atomisers}
- A61M 15/0065: {Inhalators with dosage or measuring devices (A61M15/0028 takes precedence; dosage devices incorporated in aerosol cans B65D83/52)}
- A61M 15/08: Inhaling devices inserted into the nose
- A61M 15/007: {Mechanical counters}
- A61M 15/008: {Electronic counters}
- A61M 2202/064: Powder
- A61M 2205/18: with alarm
- A61M 2205/273: preventing reuse, e.g. of disposables
- A61M 2205/276: preventing unwanted use
- A61M 2205/3553: remote, e.g. between patient's home and doctor's office
- A61M 2205/3592: using telemetric means, e.g. radio or optical transmission
- A61M 2205/505: Touch-screens; Virtual keyboard or keypads; Virtual buttons; Soft keys; Mouse touches
- A61M 2205/6018: providing set-up signals for the apparatus configuration
- A61M 2205/6054: Magnetic identification systems
- A61M 2205/6081: Colour codes
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}

## 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.

## Claims

### Claim 1

A device for intranasal administration of a pharmaceutical composition comprising:
a reservoir and a means for discharging one or more doses of the pharmaceutical composition, wherein the reservoir contains a quantity of the pharmaceutical composition; and
wherein the pharmaceutical composition comprises:
an anti-muscarinic agent, wherein the anti-muscarinic agent is atropine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.1 mg to about 10 mg of the atropine or the pharmaceutically acceptable salt thereof;
a cholinesterase reactivator, wherein the cholinesterase reactivator is 2-pyridine aldoxime methyl chloride, wherein the pharmaceutical composition provides a dose of about 1 mg to about 1000 mg of the 2-pyridine aldoxime methyl chloride;
a vasoactive agent, wherein the vasoactive agent is epinephrine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.01 mg to about 10 mg of the epinephrine or the pharmaceutically acceptable salt thereof; and
an anti-convulsant agent, wherein the anti-convulsant agent is diazepam or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.1 mg to about 20 mg of the diazepam or the pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The device of claim 1, wherein the device includes a nasal probe, and wherein the nasal probe is operable to be replaced between discharges.

### Claim 3 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises a vasodilator, wherein the vasodilator is phentolamine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.01 mg to about 10 mg of the phentolamine or the pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises a catechol-o-methyl transferase (COMT) inhibitor.

### Claim 5 (depends on 4)

The device of claim 4, wherein the COMT inhibitor is entacapone or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 5 mg to about 200 mg of the entacapone or the pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises an anticaking agent.

### Claim 7 (depends on 6)

The device of claim 6, wherein the anticaking agent is tribasic calcium phosphate.

### Claim 8 (depends on 1)

The device of claim 1, wherein the atropine or the pharmaceutically acceptable salt thereof, the 2-pyridine aldoxime methyl chloride, the epinephrine or the pharmaceutically acceptable salt thereof, and/or the diazepam or the pharmaceutically acceptable salt thereof are particles having a median particle diameter of about 30 μM.

### Claim 9 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises at least one antihistamine.

### Claim 10 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises at least one steroid.

### Claim 11 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises a carrier.

### Claim 12 (depends on 11)

The device of claim 11, wherein the carrier comprises at least one cellulose and/or at least one starch.

### Claim 13 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises one or more agents selected from a group consisting of an excipient, a preservative, a humectant, a thickening agent, a solubilizing agent, a taste-masking agent, a scent-masking agent, an antioxidant enzyme, a viscosity enhancing agent, a dispersing agent, a surfactant, a chelator, an antihistamine, a colorant, or any combination thereof.

### Claim 14 (depends on 1)

The device of claim 1, wherein the pharmaceutical composition further comprises one or more agents selected from a group consisting of a mucosal permeation or penetration enhancer, a mucoadhesive, a mucosal transit slowing agent, a mucosal transport enhancer, or any combination thereof.

### Claim 15

A kit for intranasal administration of a pharmaceutical composition comprising:
at least one device, wherein each of the at least one device includes a reservoir and a means for discharging one or more doses of the pharmaceutical composition, wherein the reservoir contains a quantity of the pharmaceutical composition; and
wherein the pharmaceutical composition comprises:
an anti-muscarinic agent, wherein the anti-muscarinic agent is atropine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.1 mg to about 10 mg of the atropine or the pharmaceutically acceptable salt thereof;
a cholinesterase reactivator, wherein the cholinesterase reactivator is 2-pyridine aldoxime methyl chloride, wherein the pharmaceutical composition provides a dose of about 1 mg to about 1000 mg of the 2-pyridine aldoxime methyl chloride;
a vasoactive agent, wherein the vasoactive agent is epinephrine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.01 mg to about 10 mg of the epinephrine or the pharmaceutically acceptable salt thereof; and
an anti-convulsant agent, wherein the anti-convulsant agent is diazepam or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.1 mg to about 20 mg of the diazepam or the pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 15)

The kit of claim 15, wherein the at least one device is enclosed in a pouch or a hard case.

### Claim 17 (depends on 16)

The kit of claim 16, wherein the pouch or the hard case is water resistant or waterproof.

### Claim 18 (depends on 16)

The kit of claim 16, wherein the pouch or the hard case includes an exterior finish comprising a camouflage.

### Claim 19 (depends on 16)

The kit of claim 16, wherein the pouch and/or the hard case is MOLLE-compatible.

### Claim 20

A device for intranasal administration of a pharmaceutical composition comprising:
a reservoir and a means for discharging one or more doses of the pharmaceutical composition, wherein the reservoir contains a quantity of the pharmaceutical composition; and
wherein the pharmaceutical composition comprises:
an anti-muscarinic agent, wherein the anti-muscarinic agent is atropine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.1 mg to about 10 mg of the atropine or the pharmaceutically acceptable salt thereof;
a cholinesterase reactivator, wherein the cholinesterase reactivator is 2-pyridine aldoxime methyl chloride, wherein the pharmaceutical composition provides a dose of about 1 mg to about 1000 mg of the 2-pyridine aldoxime methyl chloride;
a vasoactive agent, wherein the vasoactive agent is epinephrine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.01 mg to about 10 mg of the epinephrine or the pharmaceutically acceptable salt thereof;
an anti-convulsant agent, wherein the anti-convulsant agent is diazepam or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.1 mg to about 20 mg of the diazepam or the pharmaceutically acceptable salt thereof;
a vasodilator, wherein the vasodilator is phentolamine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides a dose of about 0.01 mg to about 10 mg of the phentolamine or the pharmaceutically acceptable salt thereof; and
a carrier.