# US 12,599,576 B2 · Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan

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- Number: US 12,599,576 B2
- Document ID: US12599576B2
- Status: Granted
- Kind: B2
- Application number: 19/264,750
- Filed: 2025-07-09
- Published: 2025-10-30
- Granted: 2026-04-14
- Earliest claimed: 2022-06-30
- Assignees: Antecip Bioventures II LLC
- Applicants: Antecip Bioventures II LLC
- Inventors: Herriot Tabuteau
- Web page: https://patentgrep.com/patent/US12599576B2

## CPC

- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2086: {Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat (active cores with a complete drug-free outer coat A61K9/28)}
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- 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

Disclosed herein is a method of safely treating a nervous system condition with a combination of dextromethorphan and bupropion. This method is intended for patients having a neurological condition or a psychiatric condition, such as major depressive disorder, and a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype.

## Claims

### Claim 1

A method of improving one or more behaviors associated with agitation in Alzheimer's disease in a CYP2D6 poor metabolizer comprising, selecting a human patient known to be a poor CYP2D6 metabolizer who is experiencing agitation in Alzheimer's disease, and administering, once daily in the morning for at least two weeks to the human patient, a dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein the dextromethorphan Cmax of the human patient is 198% to 454% that of the dextromethorphan Cmax of extensive or ultra-extensive CYP2D6 metabolizers, wherein the one or more behaviors associated with agitation in Alzheimer's disease comprise incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, kicking, or a combination thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the dextromethorphan Cmax of the human patient is about 300% that of the dextromethorphan Cmax of extensive or ultra-extensive CYP2D6 metabolizers.

### Claim 3 (depends on 1)

The method of claim 1, wherein the dosage form is a bilayer tablet.

### Claim 4 (depends on 1)

The method of claim 1, wherein the dosage form is orally administered.

### Claim 5 (depends on 1)

The method of claim 1, wherein once-daily administration for 8 days avoids the human patient having an about 3-fold increase in the Cmax of dextromethorphan as compared to the Cmax of dextromethorphan that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra-extensive CYP2D6 metabolizer.

### Claim 6 (depends on 1)

The method of claim 1, wherein once-daily administration for 8 days avoids the human patient having an about 3.4-fold increase in the AUC0-12 of dextromethorphan as compared to the AUC0-12 of dextromethorphan that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra-extensive CYP2D6 metabolizer.

### Claim 7 (depends on 1)

The method of claim 1, wherein the dextromethorphan is in an immediate-release formulation.

### Claim 8 (depends on 7)

The method of claim 7, wherein the bupropion is in an extended-release formulation.

### Claim 9 (depends on 1)

The method of claim 1, wherein the dosage form further comprises carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate, L-cysteine hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, yellow iron oxide, or a combination thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein twice-daily administration of the dosage form to the human patient for 8 days would result in the human patient having about same AUC0-12 of bupropion as compared to the AUC0-12 of bupropion that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra-extensive CYP2D6 metabolizer.

### Claim 11 (depends on 1)

The method of claim 1, wherein twice-daily administration of the dosage form to the human patient for 8 days would result in the human patient having about same Cmax of bupropion as compared to the Cmax of bupropion that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra-extensive CYP2D6 metabolizer.

### Claim 12

A method of improving one or more behaviors associated with agitation in Alzheimer's disease in a CYP2D6 poor metabolizer comprising, selecting a human patient known to be a poor CYP2D6 metabolizer who is experiencing agitation in Alzheimer's disease, and administering, once daily in the morning for at least four weeks to the human patient, a dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein the dextromethorphan Cmax of the human patient is 198% to 454% that of the dextromethorphan Cmax of extensive or ultra-extensive CYP2D6 metabolizers, wherein the one or more behaviors associated with agitation in Alzheimer's disease comprise incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, kicking, or a combination thereof.

### Claim 13 (depends on 12)

The method of claim 12, wherein the dextromethorphan Cmax of the human patient is about 300% that of the dextromethorphan Cmax of extensive or ultra-extensive CYP2D6 metabolizers.

### Claim 14 (depends on 12)

The method of claim 12, wherein the dosage form is a bilayer tablet.

### Claim 15 (depends on 12)

The method of claim 12, wherein the dosage form is orally administered.

### Claim 16 (depends on 12)

The method of claim 12, wherein the dextromethorphan is in an immediate-release formulation.

### Claim 17 (depends on 16)

The method of claim 16, wherein the bupropion is in an extended-release formulation.

### Claim 18 (depends on 12)

The method of claim 12, wherein the dosage form further comprises carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate, L-cysteine hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, yellow iron oxide, or a combination thereof.

### Claim 19 (depends on 12)

The method of claim 12, wherein twice-daily administration of the dosage form to the human patient for 8 days would result in the human patient having about same AUC0-12 of bupropion as compared to the AUC0-12 of bupropion that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra-extensive CYP2D6 metabolizer.

### Claim 20 (depends on 12)

The method of claim 12, wherein twice-daily administration of the dosage form to the human patient for 8 days would result in the human patient having about same Cmax of bupropion as compared to the Cmax of bupropion that would result after 8 days of twice daily administration of the dosage form to a human patient who is an extensive or ultra-extensive CYP2D6 metabolizer.