# US 9,517,231 B2 · Methods and pharmaceutical compositions for the treatment of symptoms of anxiety and panic using beta adrenergic receptor antagonist and muscarinic receptor antagonist combinations

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- Number: US 9,517,231 B2
- Document ID: US9517231B2
- Status: Granted
- Kind: B2
- Application number: 14/803,434
- Filed: 2015-07-20
- Published: 2016-01-28
- Granted: 2016-12-13
- Earliest claimed: 2014-07-22
- Assignees: Thomas P. Dooley
- Applicants: Thomas P. Dooley
- Inventors: Thomas P. Dooley
- Web page: https://patentgrep.com/patent/US9517231B2

## CPC

- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0031: {Rectum, anus}
- A61K 9/0034: {Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 9/02: Suppositories; Bougies; Bases therefor; {Ovules}(apparatus for making A61J3/08; devices for introducing into the body A61M31/00)
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377)
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 25/22: Anxiolytics
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is focused primarily toward pro re nata (“as needed”) treatments for a psychiatric condition or disorder or the symptoms thereof, including the symptoms of acute anxiety and panic in living animals, including humans. The present invention encompasses pharmaceutical compositions as combination therapies containing at least one beta adrenergic receptor antagonist and at least one muscarinic receptor antagonist. The invention provides methods for treating psychiatric condition or disorder or the symptoms thereof, including acute anxiety and panic comprising administering a pharmaceutical composition consisting essentially of a beta adrenergic receptor antagonist drug and an antiemetic muscarinic receptor antagonist drug in a therapeutically effective amount to stop or reduce the symptoms of anxiety and/or panic. The pharmaceutical compositions are administered as treatments immediately in advance of, at the onset of, or during an acute anxiety and/or panic episode.

## Claims

### Claim 1

A pharmaceutical composition for pro re nata (p.r.n.) treatment of anxiety disorders and/or the symptoms thereof, consisting essentially of a combination of at least one beta adrenergic receptor antagonist agent and/or pharmaceutically acceptable salts thereof, and at least one antiemetic muscarinic receptor antagonist agent and/or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients, wherein the at least one beta adrenergic receptor antagonist agent and the at least one antiemetic muscarinic receptor antagonist agent are combined in amounts therapeutically effective for p.r.n. symptomatic treatment of a subject and wherein the pharmaceutical composition is in a form for mucosal, sublingual, buccal, rectal, vaginal, nasal, or oral p.r.n. administration by a subject anticipating symptoms of an anxiety disorder and/or experiencing symptoms of an anxiety disorder.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the form is a liquid or semi-solid form comprising at least one penetration-enhancing solvent selected from the group consisting of ethanol, glycerol, propylene glycol, ethoxydiglycol, and dimethylsulfoxide.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the form is a solid form comprising at least one component selected from the group consisting of mannitol, a monosaccharide, a disaccharide, a bicarbonate buffer, a phosphate buffer, a binding agent, and a preservative.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent is selected from the group consisting of propranolol, atenolol, alprenolol, acebutolol, betaxolol, bisoprolol, bucindolol, celiprolol, nadolol, sotalol, esmolol, carteolol, carvedilol, mepindolol, nebivolol, oxprenolol, penbutolol, pindolol, landiolol, metoprolol, timolol, labetolol, and/or pharmaceutically acceptable salts thereof, and Eucommia extract.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one antiemetic muscarinic receptor antagonist agent is selected from the group consisting of scopolamine, diphenhydramine, meclizine, buclizine, cyclizine, hydroxyzine, pirenzepine, benztropine (benzatropine), hyoscyamine, butylscopolamine, methylscopolamine, doxylamine, promethazine, trihexyphenidyl, orphenadrine, and/or pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent is selected from the group consisting of propranolol, atenolol, pindolol, nadolol, nebivolol, labetolol, and/or pharmaceutically acceptable salts thereof and wherein the at least one antiemetic muscarinic receptor antagonist agent is selected from the group consisting of scopolamine, diphenhydramine, orphenadrine, meclizine, hydroxyzine, promethazine, and/or pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent is selected from the group consisting of propranolol, atenolol, and/or pharmaceutically acceptable salts thereof, and Eucommia extract, and wherein the at least one antiemetic muscarinic receptor antagonist agent is selected from the group consisting of scopolamine, diphenhydramine, cyclizine, meclizine, doxylamine, orphenadrine, and/or pharmaceutically acceptable salts thereof.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent is selected from the group consisting of propranolol, atenolol, pindolol, nadolol, nebivolol, and/or pharmaceutically acceptable salts thereof and the at least one antiemetic muscarinic receptor antagonist agent is scopolamine and/or pharmaceutically acceptable salts thereof.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent and/or pharmaceutically acceptable salts thereof, is in an amount of about 10 to 100 mg/dose, and wherein the at least one antiemetic muscarinic receptor antagonist agent and/or pharmaceutically acceptable salts thereof, is in an amount of about 10 to 100 mg/dose, and wherein the at least one antiemetic muscarinic receptor antagonist agent is not scopolamine.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent and/or pharmaceutically acceptable salts thereof, is in an amount of about 10 to 100 mg/dose, and wherein the at least one antiemetic muscarinic receptor antagonist agent and/or pharmaceutically acceptable salts thereof, is scopolamine in an amount of about 0.05 to 1.0 mg/dose.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent is propranolol, atenolol, pindolol, nadolol, labetolol, or nebivolol and/or pharmaceutically acceptable salts thereof, in an amount of about 10 to 100 mg/dose for an adult, and wherein the at least one antiemetic muscarinic receptor antagonist agent is scopolamine, and/or pharmaceutically acceptable salts thereof, in an amount of about 0.05 to 1.0 mg/dose for an adult, and wherein the doses are lower for an adolescent or child, and wherein the pharmaceutical composition is in a form for p.r.n. administration by a subject by a route of delivery selected from the group consisting of mucosal, sublingual, buccal, rectal, vaginal, nasal, and oral routes.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one beta adrenergic receptor antagonist agent is propranolol or atenolol, and/or pharmaceutically acceptable salts thereof, in an amount of about 10 to 100 mg/dose for an adult, and wherein the at least one antiemetic muscarinic receptor antagonist agent is scopolamine, and/or pharmaceutically acceptable salts thereof, in an amount of about 0.05 to 1.0 mg/dose for an adult, and wherein the doses are lower for an adolescent or child.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one antiemetic muscarinic receptor antagonist agent is scopolamine, and wherein the at least one beta adrenergic receptor antagonist agent and the at least one antiemetic muscarinic receptor antagonist agent are combined in amounts therapeutically effective for p.r.n. symptomatic treatment in a ratio in a range of 150:1 to 40:1 (beta adrenergic receptor antagonist agent:
antiemetic muscarinic receptor antagonist agent).

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1, wherein the at least one antiemetic muscarinic receptor antagonist agent is scopolamine, and wherein the at least one beta adrenergic receptor antagonist agent and the at least one antiemetic muscarinic receptor antagonist agent are combined in amounts therapeutically effective for p.r.n. symptomatic treatment in a ratio of approximately 80:1 (beta adrenergic receptor antagonist agent:antiemetic muscarinic receptor antagonist agent).