# US 2008/0305167 A2 · Tamper-resistant oral opioid agonist formulations

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- Number: US 2008/0305167 A2
- Document ID: US20080305167A2
- Status: Published application
- Kind: A2
- Application number: 10/700,906
- Filed: 2003-11-04
- Published: 2008-12-11
- Earliest claimed: 2000-02-08
- Assignees: Purdue Pharma L.P.
- Inventors: Benjamin Oshlack; Curtis Wright; J. David Haddox
- Web page: https://patentgrep.com/patent/US20080305167A2

## CPC

- A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)}
- A61K 9/0043: {Nose}
- 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 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/50: Microcapsules {having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals (A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167)}
- A61K 9/501: {Inorganic compounds}
- A61K 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 9/5078: {with drug-free core}
- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 9/7053: {obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene}
- A61K 9/7061: {Polyacrylates}
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 39/00: General protective or antinoxious agents
- 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

Disclosed is an oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the amount of antagonist released from said dosage form after tampering to the amount of said antagonist released from said intact dosage form is about 4:1 or greater, based on the in-vitro dissolution at 1 hour of said dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C. wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.

## Claims

### Claim 1

An oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the amount of antagonist released from said dosage form after tampering to the amount of said antagonist released from said intact dosage form is about 4:1 or greater, based on the in-vitro dissolution at 1 hour of said dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C. wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.

### Claim 2

An oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the amount of antagonist released from said dosage form after tampering to the amount of said antagonist released from said intact dosage form is about 4:1 or greater, based on the in-vitro dissolution at 1 hour of said dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C. wherein said antagonist is in the form of multiparticulates individually coated with a sequestering material which substantially prevents release of the antagonist.

### Claim 3

An oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the amount of antagonist released from said dosage form after tampering to the amount of said antagonist released from said intact dosage form is about 4:1 or greater, based on the in-vitro dissolution at 1 hour of said dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C. wherein said antagonist is dispersed in a matrix comprising a sequestering material which substantially prevents the release of the antagonist.

### Claim 4

An oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the amount of antagonist contained in said intact dosage form to the amount of said antagonist released from said intact dosage form after 1 hour is about 4:1 or greater, based on the in-vitro dissolution at 1 hour of said dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C. wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.

### Claim 5

An oral dosage form comprising (i) an opioid agonist in a releasable form; and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the amount of antagonist released from said intact dosage form after 1 hour is less than an amount bioequivalent to 0.25 mg naltrexone and the amount of said antagonist released after 1 hour from said dosage form after tampering is an amount bioequivalent to 0.25 mg naltrexone or more, said release based on the dissolution at 1 hour of said dosage from in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C., wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.

### Claim 6

An oral dosage form comprising (i) an opioid agonist in a releasable form; and (ii) sequestered naltrexone or a pharmaceutically acceptable sat thereof which is substantially not released when the dosage form is administered intact, such that the amount of naltexone released from said intact dosage form after 1 hour is less than 0.25 mg and the amount of said naltrexone released after 1 hour from said dosage form after tampering is 0.25 mg or more, said release based on the dissolution at 1 hour of said dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C., wherein said agonist and naltrexone are interdispersed and are not isolated from each other in two distinct layers.

### Claim 7

An oral dosage form comprising (i) a therapeutic effect of an opioid agonist; and (ii) a sequestered opioid antagonist, such that at 1 hour after oral administration, said dosage form releases not more than 25% of said antagonist, said dosage form providing analgesia and said released antagonist not affecting analgesic efficacy, wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.

### Claim 8

An oral dosage form comprising: (i) an opioid agonist in a releasable form; and an (ii) opioid antagonist in substantially non-releasable form wherein said antagonist is in the form of multiparticulates individually coated with a material that substantially prevents release of the antagonist.

### Claim 9

An oral dosage form comprising: (i) an opioid agonist in a releasable form; and an (ii) opioid antagonist in substantially non-releasable form wherein said antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.

### Claim 10 (depends on 1, 2, 3, 4)

The oral dosage form of claims 1-4 wherein said ratio is 10:1 or greater.

### Claim 11 (depends on 1, 2, 3, 4)

The oral dosage form of claims 1-4 wherein said ratio is 50:1 or greater.

### Claim 12 (depends on 1, 2, 3, 4)

The oral dosage form of claims 1-4 wherein said ratio is 100:1 or greater.

### Claim 13 (depends on 6)

The oral dosage form of claim 6 wherein said intact dosage form releases at least 0.025 mg naltrexone at 1 hour.

### Claim 14 (depends on 1, 2, 3, 4, 5, 7, 8, 9)

The oral dosage form of claims 1-5 and 7-9 wherein said intact dosage form provides at least an amount of antagonist bioequivalent to 0.025 mg naltrexone at 1 hour.

### Claim 15 (depends on 5)

The oral dosage form of claim 5 wherein the amount of antagonist released after 1 hour from said tampered dosage form is an amount bioequivalent to 0.5 mg naltrexone or more.

### Claim 16 (depends on 5, 15)

The oral dosage form of claims 5 and 15 wherein the amount of antagonist released after 1 hour from said intact dosage form is an amount bioequivalent to 0.125 mg naltrexone or less.

### Claim 17 (depends on 6)

The oral dosage form of claim 6 wherein the amount of antagonist released after 1 hour from said tampered dosage form is 0.5 mg naltrexone or more.

### Claim 18 (depends on 6, 17)

The oral dosage form of claims 6 and 17 wherein the amount of antagonist released after 1 hour from said intact dosage form is 0.125 mg naltrexone or less.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The oral dosage form of claims 1-9, wherein the opioid agonist is selected from the group consisting of morphine, hydromolphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 20 (depends on 19)

The oral dosage form of claim 19, wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.

### Claim 21 (depends on 1, 2, 3, 4, 5, 7, 8, 9)

The oral dosage form of claims 1-5 and 7-9, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 22 (depends on 21)

The oral dosage form of claim 21, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 23 (depends on 22)

The oral dosage form of claim 22, wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 2, 8)

The oral dosage form of claims 2 and 8, wherein the material comprises a cellulose polymer or an acrylic polymer that is insoluble in the gastrointestinal tract and impermeable to the opioid antagonist contained within the coating.

### Claim 25 (depends on 24)

The oral dosage form of claim 24, wherein the cellulose polymer is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, and mixtures thereof.

### Claim 26 (depends on 24)

The oral dosage form of claim 24, wherein the acrylic polymer is selected from the group consisting of acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The oral dosage form of claims 1-9, wherein the dosage form provides sustained-release of the opioid agonist.

### Claim 28 (depends on 27)

The oral dosage form of claim 27, wherein the dosage form is a sustained-release tablet or a sustained-release capsule.

### Claim 29 (depends on 2, 8)

The oral dosage form of claim 2 and 8 wherein said multiparticulates are in the form of inert beads coated with said antagonist and overcoated with said material.

### Claim 30 (depends on 2, 8)

The oral dosage form of claims 2 and 8 wherein said multiparticulates are in the form of a granulation comprising said antagonist and said material.

### Claim 31 (depends on 2, 8)

The oral dosage form of claims 2 and 8 wherein said multiparticulates are dispersed in a matrix comprising said opioid agonist.

### Claim 32 (depends on 2, 8)

The oral dosage form of claims 2 and 8 wherein said multiparticulates are contained in a capsule with said opioid agonist.

### Claim 33 (depends on 3, 9)

The oral dosage form of claims 3 and 9 wherein said matrix is in the form of pellets.

### Claim 34 (depends on 33)

The oral dosage form of claim 33 wherein said pellets are dispersed in a matrix comprising said opioid agonist.

### Claim 35 (depends on 33)

The oral dosage form of claim 33 wherein said pellets are contained in a capsule with said opioid agonist.

### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The oral dosage form of claims 1-9 wherein said tampering is by crushing.

### Claim 37 (depends on 27)

The oral dosage form of claim 27 wherein said tampering is in a manner as to obtain an immediate release of said agonist.

### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The oral dosage form of claims 1-9 wherein said tampering is to make the agonist available for inappropriate use.

### Claim 39 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The oral dosage form of claims 1-9 wherein said antagonist does not significantly affect analgesia provided by the agonist.

### Claim 40 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

A method of decreasing the abuse of an opioid agonist in an oral dosage form, comprising incorporating said opioid agonist into a dosage form of claims 1-9.

### Claim 41

A dosage form comprising:
(a) an opioid agonist; and
(b) naltrexone in a substantially non-releasable form; wherein the agonist and naltrexone are at least partially interdispersed.

### Claim 42 (depends on 41)

The dosage form of claim 41 wherein the opioid agonist is oxycodone, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, salts thereof, or mixtures thereof.

### Claim 43 (depends on 42)

The dosage form of claim 42 wherein the opioid agonist is oxycodone hydrochloride.

### Claim 44 (depends on 42)

The dosage form of claim 42 wherein the opioid agonist is hydrocodone bitartrate.

### Claim 45 (depends on 42)

The dosage form of claim 42 wherein the opioid agonist is hydromorphone hydrochloride.

### Claim 46 (depends on 41)

The dosage form of claim 41 wherein at least part of the naltrexone is in a matrix.

### Claim 47 (depends on 41)

The dosage form of claim 41 wherein at least part of the naltrexone is in a coated bead.

### Claim 48 (depends on 41)

The dosage form of claim 41 wherein the naltrexone in a substantially non-releasable form is adapted to release less than 15% by weight of the naltrexone in vivo after 36 hours.

### Claim 49 (depends on 48)

The dosage form of claim 48 wherein the naltrexone in a substantially non-releasable form is adapted to release less than 8% by weight of the naltrexone in vivo after 36 hours.

### Claim 50 (depends on 49)

The dosage form of claim 49 wherein the naltrexone in a substantially non-releasable form is adapted to release less than 1% by weight of the naltrexone in vivo after 36 hours.

### Claim 51 (depends on 41)

The dosage form of claim 41 wherein the naltrexone in a substantially non-releasable form is adapted to release less than 3% by weight of the naltrexone in vivo after 1 hour.

### Claim 52 (depends on 41)

The dosage form of claim 41 wherein the naltrexone in a substantially non-releasable form is adapted to release less than 1.0% by weight of the naltrexone in vivo after 1 hour.

### Claim 53 (depends on 41)

The dosage form of claim 41 wherein the naltrexone in a substantially non-releasable form is adapted to release less than 0.5% by weight of the naltrexone in vivo after 1 hour.

### Claim 54

A dosage form comprising:
(a) an opioid agonist; and
(b) an orally-bioavailable opioid antagonist in a substantially non-releasable form;

### Claim 55 (depends on 54)

The dosage form of claim 54 wherein the agonist and antagonist are at least partially interdispersed.

### Claim 56 (depends on 54)

The dosage form of claim 54 wherein the orally-bioavailable opioid antagonist is naltrexone, or a salt thereof.

### Claim 57 (depends on 54)

The dosage form of claim 54 wherein the opioid agonist is oxycodone, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, or salts thereof or mixtures thereof.

### Claim 58 (depends on 54)

The dosage form of claim 54 wherein at least part of the antagonist is in a matrix.

### Claim 59 (depends on 54)

The dosage form of claim 54 wherein at least part of the antagonist is in a coated bead.

### Claim 60

A method of preparing an oral dosage form comprising pretreating an opioid antagonist to render it substantially non-releasable; and combining the pretreated antagonist with a releasable form of an opioid agonist.

### Claim 61 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 41, 54)

A method of treating pain comprising administering to a human patient a dosage form of claims 1-9, 41 or 54.