# US 8,465,774 B2 · Sequestered antagonist formulations

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- Number: US 8,465,774 B2
- Document ID: US8465774B2
- Status: Granted
- Kind: B2
- Application number: 11/352,900
- Filed: 2006-02-13
- Published: 2006-08-17
- Granted: 2013-06-18
- Earliest claimed: 2001-08-06
- Assignees: Purdue Pharma L.P.
- Applicants: Christopher Breder; Benjamin Oshlack; Curtis Wright
- Inventors: Christopher Breder; Benjamin Oshlack; Curtis Wright
- Web page: https://patentgrep.com/patent/US8465774B2

## CPC

- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 9/0087: {Galenical forms not covered by A61K9/02 - A61K9/7023}
- 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 9/5084: {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 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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 mean Cmax of the antagonist after single dose oral administration of the dosage form after tampering to the mean Cmax of antagonist after single dose oral administration of an intact dosage form is at least 1.5:1.

## Claims

### Claim 1

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the mean Cmax of the antagonist after single dose oral administration of the dosage form after tampering to the mean Cmax of antagonist after single dose oral administration of an intact dosage form is at least 1.5:1,
wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 2 (depends on 1)

The dosage form of claim 1 wherein said ratio is at least 3:1.

### Claim 3 (depends on 1)

The dosage form of claim 1 wherein said ratio is at least 4.5:1.

### Claim 4 (depends on 1)

The dosage form of claim 1 wherein said ratio is at least 8:1.

### Claim 5 (depends on 1)

The dosage form of claim 1 wherein said ratio is at least 10:1.

### Claim 6 (depends on 1)

The dosage form of claim 1 wherein said ratio is at least 100:1.

### Claim 7 (depends on 1)

The dosage form of claim 1 wherein said ratio is less than about 1000:1.

### Claim 8 (depends on 1)

The oral dosage form of claim 1, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, 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 9 (depends on 8)

The oral dosage form of claim 8, wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 10)

The oral dosage form of claim 10, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 12 (depends on 1)

The oral dosage form of claim 1, wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

The dosage form of claim 12 wherein the intact dosage form provides a Cmax of naltrexone of 30 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 14 (depends on 12)

The dosage form of claim 12 wherein the intact dosage form provides a Cmax of naltrexone of 15 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 15 (depends on 12)

The dosage form of claim 12 wherein the intact dosage form provides a Cmax of naltrexone of 10 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 16 (depends on 12)

The dosage form of claim 12 wherein the intact dosage form provides a Cmax of naltrexone of 6 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 17 (depends on 12)

The dosage form of claim 12 wherein the intact dosage form provides a Cmax of naltrexone of 3 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 18 (depends on 12)

The dosage form of claim 12 wherein the intact dosage form provides a Cmax of naltrexone of 1 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 19 (depends on 1)

The dosage form of claim 1, wherein the sequestering material comprises a cellulose polymer, and the inert beads are coated with said antagonist and overcoated with the sequestering material.

### Claim 20 (depends on 1)

The oral dosage form of claim 1 wherein said tampering is by crushing.

### Claim 21 (depends on 1)

The oral dosage form of claim 1 wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.

### Claim 22

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the mean Cmax of the antagonist after single dose oral administration of an immediate release reference product containing an equivalent amount of antagonist to the mean Cmax of antagonist after single dose oral administration of an intact dosage form is at least 2:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 23 (depends on 22)

The dosage form of claim 22 wherein said ratio is at least 4:1.

### Claim 24 (depends on 22)

The dosage form of claim 22 wherein said ratio is at least 8:1.

### Claim 25 (depends on 22)

The dosage form of claim 22 wherein said ratio is at least 12:1.

### Claim 26 (depends on 22)

The dosage form of claim 22 wherein said ratio is at least 25:1.

### Claim 27 (depends on 22)

The dosage form of claim 22 wherein said ratio is at least 150:1.

### Claim 28 (depends on 22)

The dosage form of claim 22 wherein said ratio is less than about 2000:1.

### Claim 29 (depends on 22)

The oral dosage form of claim 22, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, 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 30 (depends on 29)

The oral dosage form of claim 29, wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.

### Claim 31 (depends on 22)

The oral dosage form of claim 22, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 32 (depends on 31)

The oral dosage form of claim 31, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 33 (depends on 22)

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

### Claim 34 (depends on 33)

The dosage form of claim 33 wherein the intact dosage form provides a Cmax of naltrexone of 30 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 35 (depends on 33)

The dosage form of claim 33 wherein the intact dosage form provides a Cmax of naltrexone of 15 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 36 (depends on 33)

The dosage form of claim 33 wherein the intact dosage form provides a Cmax of naltrexone of 10 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 37 (depends on 33)

The dosage form of claim 33 wherein the intact dosage form provides a Cmax of naltrexone of 6 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 38 (depends on 33)

The dosage form of claim 33 wherein the intact dosage form provides a Cmax of naltrexone of 3 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 39 (depends on 33)

The dosage form of claim 33 wherein the intact dosage form provides a Cmax of naltrexone of 1 pg/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 40 (depends on 22)

The dosage form of claim 22, wherein the sequestering material comprises a cellulose polymer, and the inert beads are coated with said antagonist and overcoated with the sequestering material.

### Claim 41 (depends on 22)

The oral dosage form of claim 22 wherein said tampering is by crushing.

### Claim 42 (depends on 22)

The oral dosage form of claim 22 wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.

### Claim 43

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the mean AUCt of the antagonist after single dose oral administration of the dosage form after tampering to the mean AUCt of antagonist after single dose oral administration of an intact dosage form is at least 1.5:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 44 (depends on 43)

The dosage form of claim 43 wherein said ratio is at least 3:1.

### Claim 45 (depends on 43)

The dosage form of claim 43 wherein said ratio is at least 4.5:1.

### Claim 46 (depends on 43)

The dosage form of claim 43 wherein said ratio is at least 8:1.

### Claim 47 (depends on 43)

The dosage form of claim 43 wherein said ratio is at least 10:1.

### Claim 48 (depends on 43)

The dosage form of claim 43 wherein said ratio is at least 100:1.

### Claim 49 (depends on 43)

The dosage form of claim 43 wherein said ratio is less than about 1000:1.

### Claim 50 (depends on 43)

The oral dosage form of claim 43, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, 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 51 (depends on 50)

The oral dosage form of claim 50, wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.

### Claim 52 (depends on 43)

The oral dosage form of claim 43, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 53 (depends on 52)

The oral dosage form of claim 52, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 54 (depends on 43)

The oral dosage form of claim 43, wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.

### Claim 55 (depends on 54)

The dosage form of claim 54 wherein the intact dosage form provides an AUCt of naltrexone of 400 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 56 (depends on 54)

The dosage form of claim 54 wherein the intact dosage form provides an AUCt of naltrexone of 350 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 57 (depends on 54)

The dosage form of claim 54 wherein the intact dosage form provides an AUCt of naltrexone of 225 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 58 (depends on 54)

The dosage form of claim 54 wherein the intact dosage form provides an AUCt of naltrexone of 100 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 59 (depends on 54)

The dosage form of claim 54 wherein the intact dosage form provides an AUCt of naltrexone of 50 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 60 (depends on 54)

The dosage form of claim 54 wherein the intact dosage form provides an AUCt of naltrexone of 25 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 61 (depends on 43)

The dosage form of claim 43, wherein the sequestering material comprises a cellulose polymer, and the inert beads are coated with said antagonist and overcoated with the sequestering material.

### Claim 62 (depends on 43)

The oral dosage form of claim 43 wherein said tampering is by crushing.

### Claim 63 (depends on 43)

The oral dosage form of claim 43 wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.

### Claim 64

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the mean AUCt of the antagonist after single dose oral administration of an immediate release reference product containing an equivalent amount of antagonist to the mean AUCt of antagonist after single dose oral administration of an intact dosage form is at least 1.6:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 65 (depends on 64)

The dosage form of claim 64 wherein said ratio is at least 4:1.

### Claim 66 (depends on 64)

The dosage form of claim 64 wherein said ratio is at least 7:1.

### Claim 67 (depends on 64)

The dosage form of claim 64 wherein said ratio is at least 12:1.

### Claim 68 (depends on 64)

The dosage form of claim 64 wherein said ratio is at least 25:1.

### Claim 69 (depends on 64)

The dosage form of claim 64 wherein said ratio is at least 150:1.

### Claim 70 (depends on 64)

The dosage form of claim 64 wherein said ratio is less than about 2000:1.

### Claim 71 (depends on 64)

The oral dosage form of claim 64, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, 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 72 (depends on 71)

The oral dosage form of claim 71, wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.

### Claim 73 (depends on 64)

The oral dosage form of claim 64, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 74 (depends on 73)

The oral dosage form of claim 73, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 75 (depends on 64)

The oral dosage form of claim 64, wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.

### Claim 76 (depends on 75)

The dosage form of claim 75 wherein the intact dosage form provides an AUCt of naltrexone of 400 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 77 (depends on 75)

The dosage form of claim 75 wherein the intact dosage form provides an AUCt of naltrexone of 350 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 78 (depends on 75)

The dosage form of claim 75 wherein the intact dosage form provides an AUCt of naltrexone of 225 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 79 (depends on 75)

The dosage form of claim 75 wherein the intact dosage form provides an AUCt of naltrexone of 100 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 80 (depends on 75)

The dosage form of claim 75 wherein the intact dosage form provides an AUCt of naltrexone of 50 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 81 (depends on 75)

The dosage form of claim 75 wherein the intact dosage form provides an AUCt of naltrexone of 25 pg*h/ml or less based on a dosage form containing 1 mg of naltrexone hydrochloride or an equivalent amount of naltrexone base or a pharmaceutically acceptable salt thereof other than the hydrochloride salt.

### Claim 82 (depends on 64)

The dosage form of claim 64, wherein the sequestering material comprises a cellulose polymer, and the inert beads are coated with said antagonist and overcoated with the sequestering material.

### Claim 83 (depends on 64)

The oral dosage form of claim 64 wherein said tampering is by crushing.

### Claim 84 (depends on 64)

The oral dosage form of claim 64 wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.

### Claim 85

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the mean Tmax of the antagonist after single dose oral administration of the intact dosage form to the mean Tmax of antagonist after single dose oral administration of a dosage form after tampering is at least 1.5:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 86 (depends on 85)

The dosage form of claim 85 wherein said ratio is at least 3:1.

### Claim 87 (depends on 85)

The dosage form of claim 85 wherein said ratio is at least 4:1.

### Claim 88 (depends on 85)

The dosage form of claim 85 wherein said ratio is at least 8:1.

### Claim 89 (depends on 85)

The dosage form of claim 85 wherein said ratio is at least 10:1.

### Claim 90 (depends on 85)

The dosage form of claim 85 wherein said ratio is at least 50:1.

### Claim 91 (depends on 85)

The dosage form of claim 85 wherein said ratio is less than about 100:1.

### Claim 92 (depends on 85)

The oral dosage form of claim 85, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, 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 93 (depends on 92)

The oral dosage form of claim 92, wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.

### Claim 94 (depends on 85)

The oral dosage form of claim 85, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 95 (depends on 94)

The oral dosage form of claim 94, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 96 (depends on 85)

The oral dosage form of claim 85, wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.

### Claim 97 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 0.75 hours to about 36 hours.

### Claim 98 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 1 hour to about 30 hours.

### Claim 99 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 2 hour to about 20 hours.

### Claim 100 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 3 hours to about 20 hours.

### Claim 101 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 5 hours to about 15 hours.

### Claim 102 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 6 hours to about 10 hours.

### Claim 103 (depends on 84)

The dosage form of claim 84, wherein the sequestering material comprises a cellulose polymer, and the inert beads are coated with said antagonist and overcoated with the sequestering material.

### Claim 104 (depends on 84)

The oral dosage form of claim 84 wherein said tampering is by crushing.

### Claim 105 (depends on 84)

The oral dosage form of claim 84 wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.

### Claim 106

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the mean Tmax of the antagonist after single dose oral administration of the intact dosage form to the mean Tmax of antagonist after single dose oral administration of an immediate release reference standard is at least 2, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 107 (depends on 106)

The dosage form of claim 106 wherein said ratio is at least 4:1.

### Claim 108 (depends on 106)

The dosage form of claim 106 wherein said ratio is at least 10:1.

### Claim 109 (depends on 106)

The dosage form of claim 106 wherein said ratio is at least 20:1.

### Claim 110 (depends on 106)

The dosage form of claim 106 wherein said ratio is at least 50:1.

### Claim 111 (depends on 106)

The dosage form of claim 106 wherein said ratio is at least 100:1.

### Claim 112 (depends on 106)

The dosage form of claim 106 wherein said ratio is less than about 150:1.

### Claim 113 (depends on 106)

The oral dosage form of claim 106, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, 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 114 (depends on 113)

The oral dosage form of claim 113, wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.

### Claim 115 (depends on 106)

The oral dosage form of claim 106, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 116 (depends on 115)

The oral dosage form of claim 115, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.

### Claim 117 (depends on 106)

The oral dosage form of claim 106, wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.

### Claim 118 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 0.75 hours to about 36 hours.

### Claim 119 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 1 hour to about 30 hours.

### Claim 120 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 1 hour to about 30 hours.

### Claim 121 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 2 hours to about 20 hours.

### Claim 122 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 5 hours to about 15 hours.

### Claim 123 (depends on 96)

The dosage form of claim 96 wherein the intact dosage form provides a Tmax of naltrexone of about 6 hours to about 10 hours.

### Claim 124 (depends on 106)

The dosage form of claim 106, wherein the sequestering material comprises a cellulose polymer, and the inert beads are coated with said antagonist and overcoated with the sequestering material.

### Claim 125 (depends on 106)

The oral dosage form of claim 106 wherein said tampering is by crushing.

### Claim 126 (depends on 106)

The oral dosage form of claim 106 wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.

### Claim 127

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the Cmax of the antagonist after single dose oral administration of the dosage form to an individual patient after tampering to the Cmax of antagonist after single dose oral administration to an individual patient of an intact dosage form is at least 1.5:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 128

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the Cmax of the antagonist after single dose oral administration to an individual patient of an immediate release reference product containing an equivalent amount of antagonist to the Cmax of antagonist after single dose oral administration to an individual patient of an intact dosage form is at least 2:1, wherein all antagonist in the dosage form is in said particles of the sequestered opioid antagonist.

### Claim 129

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the AUCt of the antagonist after single dose oral administration to an individual patient of the dosage form after tampering to the AUCt of antagonist after single dose oral administration of an intact dosage form to an individual patient is at least 1.5:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 130

An oral dosage form comprising (i) particles an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the AUCt of the antagonist after single dose oral administration to an individual patient of an immediate release reference product containing an equivalent amount of antagonist to the AUCt of antagonist after single dose oral administration to an individual patient of an intact dosage form is at least 1.6:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 131

An oral dosage form comprising (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the Tmax of the antagonist after single dose oral administration to an individual patient of the intact dosage form to the Tmax of antagonist after single dose oral administration to an individual patient of an dosage form after tampering is at least 1.5:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 132

An oral dosage form comprising: (i) particles of an opioid agonist in releasable form and (ii) particles of a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact,
the particles of the sequestered opioid antagonist comprising (a) inert beads coated with the antagonist and (b) a sequestering material, such that the ratio of the Tmax of the antagonist after single dose oral administration to an individual patient of the intact dosage form to the Tmax of antagonist after single dose oral administration to an individual patient of an immediate release reference standard is at least 2:1, wherein all antagonist in the dosage form is contained within said particles of the sequestered opioid antagonist.

### Claim 133 (depends on 1, 22, 43, 64, 85, 106, 127, 128, 129, 130, 131)

The oral dosage form of any one of claims 1, 22, 43, 64, 85, 106, 127, 128, 129, 130, 131, and 132, wherein said sequestered opioid antagonist is released after tampering in an amount that will substantially block an effect of the opioid agonist when the composition has been tampered with.

### Claim 134 (depends on 133)

The oral dosage form of claim 133, wherein the effect blocked by the opioid antagonist released from the composition that has been tampered with is a euphoric effect.

### Claim 135 (depends on 133)

The oral dosage form of claim 133, wherein the opioid antagonist is not bioavailable when the composition is administered intact but is bioavailable when the composition is tampered with.

### Claim 136 (depends on 133)

The oral dosage form of claim 133, wherein said tampering is by means selected from the group consisting of crushing, shearing, grinding, chewing and dissolution in a solvent in combination with heating.

### Claim 137 (depends on 133)

The oral dosage form of claim 133, wherein said tampering is by crushing.