# US 11,998,542 B2 · Compositions and methods for reducing major adverse cardiovascular events

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- Number: US 11,998,542 B2
- Document ID: US11998542B2
- Status: Granted
- Kind: B2
- Application number: 17/099,316
- Filed: 2020-11-16
- Published: 2021-03-11
- Granted: 2024-06-04
- Earliest claimed: 2013-12-06
- Assignees: Nalpropion Pharmaceuticals LLC
- Applicants: Nalpropion Pharmaceuticals LLC
- Inventors: Preston Klassen; Kristin Taylor
- Web page: https://patentgrep.com/patent/US11998542B2

## CPC

- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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 application relates to compositions, kits, uses, systems and methods of using naltrexone and bupropion, or pharmaceutically acceptable salts thereof, for reducing the risk of adverse cardiovascular outcomes or events, including Major Adverse Cardiovascular Events (MACE) in subjects, preferably those at increased risk of adverse cardiovascular outcomes or MACE, that may be overweight or obese. The present application also relates to compositions, kits, uses, systems and methods of using naltrexone and bupropion or pharmaceutically acceptable alts thereof for treatment of overweight or obesity in subjects, preferably at increased risk of adverse cardiovasular outcomes or MACE, wherein the treatment reduce, the risk of MACE.

## Claims

### Claim 1

A method of administering naltrexone and bupropion to a subject having an increased risk of a major adverse cardiovascular event (MACE), the method comprising:
administering to the subject a daily dose of 4-50 mg of naltrexone, or a pharmaceutically acceptable salt thereof, and 50-400 mg of bupropion, or a pharmaceutically acceptable salt thereof, for a treatment period of at least 1 week, wherein the subject is a smoker.

### Claim 2 (depends on 1)

The method of claim 1, wherein the smoker is a smoker at the beginning of the treatment period.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject has a history of cardiovascular disease.

### Claim 4 (depends on 3)

The method of claim 3, wherein the subject has one or more of:
a history of documented myocardial infarction more than 3 months prior to treatment;
a history of coronary, carotid or peripheral revascularization;
angina with ischemic changes,
ECG changes on a graded exercise test;
positive cardiac imaging study;
ankle brachial index less than 0.9 within 2 years prior to treatment; or
greater than 50% stenosis of a coronary, carotid, or lower extremity artery within 2 years prior to treatment.

### Claim 5 (depends on 1)

The method of claim 1, wherein the MACE is selected from the group consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

### Claim 6 (depends on 1)

The method of claim 1, wherein the treatment period is at least 12 weeks.

### Claim 7 (depends on 1)

The method of claim 1, wherein the subject is administered:
about 8 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 90 mg of bupropion or a pharmaceutically acceptable salt thereof daily for a first week of treatment;
about 16 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 180 mg of bupropion or a pharmaceutically acceptable salt thereof daily for a second week of treatment;
about 24 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 270 mg of bupropion or a pharmaceutically acceptable salt thereof daily for a third week of treatment; and
about 32 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 360 mg of bupropion or a pharmaceutically acceptable salt thereof for the fourth and any subsequent weeks of treatment.

### Claim 8 (depends on 1)

The method of claim 1, wherein the naltrexone and bupropion, or pharmaceutically acceptable salts thereof, are administered in a sustained release formulation.

### Claim 9 (depends on 1)

The method of claim 1, wherein the naltrexone and bupropion, or pharmaceutically acceptable salts thereof, are administered in a single oral unit dosage form.

### Claim 10 (depends on 1)

The method of claim 1, wherein the naltrexone salt comprises naltrexone hydrochloride and the bupropion salt comprises bupropion hydrochloride.

### Claim 11

A method of reducing risk of a major adverse cardiovascular event (MACE) in a smoker, the method comprising:
administering to the smoker a daily dose of 4-50 mg of naltrexone, or a pharmaceutically acceptable salt thereof, and 50-400 mg of bupropion, or a pharmaceutically acceptable salt thereof, for a treatment period of at least 1 week, wherein said administering reduces the risk of MACE compared to a smoker not receiving the daily dose of naltrexone, or a pharmaceutically acceptable salt thereof, and bupropion, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein the smoker is a smoker at the beginning of the treatment period.

### Claim 13 (depends on 11)

The method of claim 11, wherein the subject has a history of cardiovascular disease.

### Claim 14 (depends on 13)

The method of claim 13, wherein the subject has one or more of:
a history of documented myocardial infarction more than 3 months prior to treatment;
a history of coronary, carotid or peripheral revascularization;
angina with ischemic changes,
ECG changes on a graded exercise test;
positive cardiac imaging study;
ankle brachial index less than 0.9 within 2 years prior to treatment; or
greater than 50% stenosis of a coronary, carotid, or lower extremity artery within 2 years prior to treatment.

### Claim 15 (depends on 13)

The method of claim 13, wherein the MACE is selected from the group consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

### Claim 16 (depends on 13)

The method of claim 13, wherein the treatment period is at least 12 weeks.

### Claim 17 (depends on 13)

The method of claim 13, wherein the subject is administered:
about 8 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 90 mg of bupropion or a pharmaceutically acceptable salt thereof daily for a first week of treatment;
about 16 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 180 mg of bupropion or a pharmaceutically acceptable salt thereof daily for a second week of treatment;
about 24 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 270 mg of bupropion or a pharmaceutically acceptable salt thereof daily for a third week of treatment; and
about 32 mg of naltrexone or a pharmaceutically acceptable salt thereof and about 360 mg of bupropion or a pharmaceutically acceptable salt thereof for the fourth and any subsequent weeks of treatment.

### Claim 18 (depends on 13)

The method of claim 13, wherein the naltrexone and bupropion, or pharmaceutically acceptable salts thereof, are administered in a sustained release formulation.

### Claim 19 (depends on 13)

The method of claim 13, wherein the naltrexone and bupropion, or pharmaceutically acceptable salts thereof, are administered in a single oral unit dosage form.

### Claim 20 (depends on 13)

The method of claim 13, wherein the naltrexone salt comprises naltrexone hydrochloride and the bupropion salt comprises bupropion hydrochloride.