# US 10,946,009 B2 · Combination dosage form of a mu opioid receptor antagonist and an opioid agent

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- Number: US 10,946,009 B2
- Document ID: US10946009B2
- Status: Granted
- Kind: B2
- Application number: 16/454,353
- Filed: 2019-06-27
- Published: 2019-10-24
- Granted: 2021-03-16
- Earliest claimed: 2015-04-02
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: Theravance Biopharma R&D IP, LLC
- Inventors: Shaoling Li; Manshiu Leung; Hao Zhang; Venkat R. Thalladi; Yun Mo
- Web page: https://patentgrep.com/patent/US10946009B2

## CPC

- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- A61K 9/282: {Organic compounds, e.g. fats}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 9/2853: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)}
- A61K 9/2893: {Tablet coating processes (mechanical aspects A61J3/06)}
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 invention provides a solid composition of the peripheral mu opioid antagonist axelopran and a combination dosage form of the mu opioid antagonist axelopran sulfate in an immediate release form and an opioid analgesic agent which may be in an extended release, sustained release, modified release, or controlled release form and methods of preparing such a combination dosage form.

## Claims

### Claim 1

A method of treating pain in a mammal, the method comprising administering to the mammal a combination dosage form comprising:
a solid dosage form comprising an opioid analgesic agent, and
an immediate release portion comprising crystalline axelopran sulfate wherein the immediate release portion is a drug overcoat layer on the solid dosage form and wherein the drug overcoat layer comprises:
(a) between about 50% and about 70% by weight axelopran sulfate,
(b) between about 12% and about 25% by weight polyvinyl alcohol,
(c) between about 12% and about 25% by weight polyethylene glycol 3350, and
(d) between about 2% and about 6% by weight ascorbic acid.

### Claim 2

A method of ameliorating a gastrointestinal side effect of opioid analgesic therapy in a mammal, the method comprising administering to the mammal a combination dosage form comprising:
a solid dosage form comprising an opioid analgesic agent, and
an immediate release portion comprising crystalline axelopran sulfate wherein the immediate release portion is a drug overcoat layer on the solid dosage form and wherein the drug overcoat layer comprises:
(a) between about 50% and about 70% by weight axelopran sulfate,
(b) between about 12% and about 25% by weight polyvinyl alcohol,
(c) between about 12% and about 25% by weight polyethylene glycol 3350, and
(d) between about 2% and about 6% by weight ascorbic acid.

### Claim 3 (depends on 2)

The method of claim 2, wherein the gastrointestinal side effect of opioid analgesic therapy is opioid induced constipation.

### Claim 4 (depends on 2)

The method of claim 2, wherein the gastrointestinal side effect of opioid analgesic therapy is delayed gastric emptying.

### Claim 5 (depends on 2)

The method of claim 2, wherein the gastrointestinal side effect of opioid analgesic therapy is abdominal discomfort.

### Claim 6 (depends on 2)

The method of claim 2, wherein the gastrointestinal side effect of opioid analgesic therapy is nausea.

### Claim 7 (depends on 2)

The method of claim 2, wherein the opioid analgesic agent is in a modified release formulation.

### Claim 8 (depends on 2)

The method of claim 2, wherein the solid dosage form comprising the opioid analgesic agent is a tablet or bead.

### Claim 9 (depends on 2)

The method of claim 2, wherein the solid dosage form comprising the opioid analgesic agent is a tablet.

### Claim 10 (depends on 2)

The method of claim 2, wherein the combination dosage form further comprises a subcoat layer between the drug overcoat layer and the solid dosage form comprising the opioid analgesic agent.

### Claim 11 (depends on 10)

The method of claim 10, wherein the subcoat layer comprises polyvinyl alcohol and polyethylene glycol.

### Claim 12 (depends on 2)

The method of claim 2, wherein the opioid analgesic agent is oxycodone or oxymorphone.

### Claim 13 (depends on 2)

The method of claim 2, wherein the combination dosage form further comprises a subcoat layer wherein the subcoat layer comprises polyvinyl alcohol and polyethylene glycol and wherein the opioid analgesic agent is oxycodone or oxymorphone.

### Claim 14 (depends on 2)

The method of claim 2, wherein the combination dosage form provides an in vitro rate of release of axelopran for less than one hour and an in vitro rate of release of the opioid analgesic agent for up to 12 hours.