Sequestered antagonist formulations

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.

What is claimed is:  
     
         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 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.  
     
     
         2 . The dosage form of  claim 1  wherein said ratio is at least 3:1.  
     
     
         3 . The dosage form of  claim 1  wherein said ratio is at least 4.5:1.  
     
     
         4 . The dosage form of  claim 1  wherein said ratio is at least 8:1.  
     
     
         5 . The dosage form of  claim 1  wherein said ratio is at least 10:1.  
     
     
         6 . The dosage form of  claim 1  wherein said ratio is at least 100:1.  
     
     
         7 . The dosage form of  claim 1  wherein said ratio is less than about 1000:1.  
     
     
         8 . 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.  
     
     
         9 . 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.  
     
     
         10 . 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.  
     
     
         11 . 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.  
     
     
         12 . The oral dosage form of  claim 1 , wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.  
     
     
         13 . 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.  
     
     
         14 . 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.  
     
     
         15 . 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.  
     
     
         16 . 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.  
     
     
         17 . 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.  
     
     
         18 . 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.  
     
     
         19 . The dosage form of  claim 1 , wherein said antagonist is in the form of multiparticulates individually coated with a material that substantially prevents release of the antagonist.  
     
     
         20 . The dosage form of  claim 1 , wherein said antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.  
     
     
         21 . The dosage form of  claim 1 , wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.  
     
     
         22 . The oral dosage form of  claim 1 , wherein said tampering is by crushing.  
     
     
         23 . The oral dosage form of  claim 1 , wherein said tampering is in a manner as to obtain an immediate release of said agonist.  
     
     
         24 . The oral dosage form of  claim 1 , wherein said tampering is to make the agonist available for inappropriate use.  
     
     
         25 . 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.  
     
     
         26 . 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 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.  
     
     
         27 . The dosage form of  claim 26  wherein said ratio is at least 4:1.  
     
     
         28 . The dosage form of  claim 26  wherein said ratio is at least 8:1.  
     
     
         29 . The dosage form of  claim 26  wherein said ratio is at least 12:1.  
     
     
         30 . The dosage form of  claim 26  wherein said ratio is at least 25:1.  
     
     
         31 . The dosage form of  claim 26  wherein said ratio is at least 150:1.  
     
     
         32 . The dosage form of  claim 26  wherein said ratio is less than about 2000:1.  
     
     
         33 . The oral dosage form of  claim 26 , 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.  
     
     
         34 . The oral dosage form of  claim 33 , wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.  
     
     
         35 . The oral dosage form of  claim 26 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         36 . The oral dosage form of  claim 35 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         37 . The oral dosage form of  claim 26 , wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.  
     
     
         38 . The dosage form of  claim 37  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.  
     
     
         39 . The dosage form of  claim 37  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.  
     
     
         40 . The dosage form of  claim 37  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.  
     
     
         41 . The dosage form of  claim 37  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.  
     
     
         42 . The dosage form of  claim 37  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.  
     
     
         43 . The dosage form of  claim 37  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.  
     
     
         44 . The dosage form of  claim 26 , wherein said antagonist is in the form of multiparticulates individually coated with a material that substantially prevents release of the antagonist.  
     
     
         45 . The dosage form of  claim 26 , wherein said antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.  
     
     
         46 . The dosage form of  claim 26 , wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.  
     
     
         47 . The oral dosage form of  claim 26 , wherein said tampering is by crushing.  
     
     
         48 . The oral dosage form of  claim 26 , wherein said tampering is in a manner as to obtain an immediate release of said agonist.  
     
     
         49 . The oral dosage form of  claim 26 , wherein said tampering is to make the agonist available for inappropriate use.  
     
     
         50 . The oral dosage form of  claim 26 , wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.  
     
     
         51 . 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 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.  
     
     
         52 . The dosage form of  claim 51  wherein said ratio is at least 3:1.  
     
     
         53 . The dosage form of  claim 51  wherein said ratio is at least 4.5:1.  
     
     
         54 . The dosage form of  claim 51  wherein said ratio is at least 8:1.  
     
     
         55 . The dosage form of  claim 51  wherein said ratio is at least 10:1.  
     
     
         56 . The dosage form of  claim 51  wherein said ratio is at least 100:1.  
     
     
         57 . The dosage form of  claim 51  wherein said ratio is less than about 1000:1.  
     
     
         58 . The oral dosage form of  claim 51 , 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.  
     
     
         59 . The oral dosage form of  claim 58 , wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.  
     
     
         60 . The oral dosage form of  claim 51 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         61 . The oral dosage form of  claim 60 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         62 . The oral dosage form of  claim 51 , wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.  
     
     
         63 . The dosage form of  claim 62  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.  
     
     
         64 . The dosage form of  claim 62  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.  
     
     
         65 . The dosage form of  claim 62  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.  
     
     
         66 . The dosage form of  claim 62  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.  
     
     
         67 . The dosage form of  claim 62  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.  
     
     
         68 . The dosage form of  claim 62  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.  
     
     
         69 . The dosage form of  claim 51 , wherein said antagonist is in the form of multiparticulates individually coated with a material that substantially prevents release of the antagonist.  
     
     
         70 . The dosage form of  claim 51 , wherein said antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.  
     
     
         71 . The dosage form of  claim 51 , wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.  
     
     
         72 . The oral dosage form of  claim 51 , wherein said tampering is by crushing.  
     
     
         73 . The oral dosage form of  claim 51 , wherein said tampering is in a manner as to obtain an immediate release of said agonist.  
     
     
         74 . The oral dosage form of  claim 51 , wherein said tampering is to make the agonist available for inappropriate use.  
     
     
         75 . The oral dosage form of  claim 51 , wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.  
     
     
         76 . 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 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.  
     
     
         77 . The dosage form of  claim 76  wherein said ratio is at least 4:1.  
     
     
         78 . The dosage form of  claim 76  wherein said ratio is at least 7:1.  
     
     
         79 . The dosage form of  claim 76  wherein said ratio is at least 12:1.  
     
     
         80 . The dosage form of  claim 76  wherein said ratio is at least 25:1.  
     
     
         81 . The dosage form of  claim 76  wherein said ratio is at least 150:1.  
     
     
         82 . The dosage form of  claim 76  wherein said ratio is less than about 2000:1.  
     
     
         83 . The oral dosage form of  claim 76 , 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.  
     
     
         84 . The oral dosage form of  claim 83 , wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.  
     
     
         85 . The oral dosage form of  claim 76 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         86 . The oral dosage form of  claim 85 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         87 . The oral dosage form of  claim 76 , wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.  
     
     
         88 . The dosage form of  claim 87  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.  
     
     
         89 . The dosage form of  claim 87  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.  
     
     
         90 . The dosage form of  claim 87  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.  
     
     
         91 . The dosage form of  claim 87  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.  
     
     
         92 . The dosage form of  claim 87  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.  
     
     
         93 . The dosage form of  claim 87  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.  
     
     
         94 . The dosage form of  claim 76 , wherein said antagonist is in the form of multiparticulates individually coated with a material that substantially prevents release of the antagonist.  
     
     
         95 . The dosage form of  claim 76 , wherein said antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.  
     
     
         96 . The dosage form of  claim 76 , wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.  
     
     
         97 . The oral dosage form of  claim 76 , wherein said tampering is by crushing.  
     
     
         98 . The oral dosage form of  claim 76 , wherein said tampering is in a manner as to obtain an immediate release of said agonist.  
     
     
         99 . The oral dosage form of  claim 76 , wherein said tampering is to make the agonist available for inappropriate use.  
     
     
         100 . The oral dosage form of  claim 76  wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.  
     
     
         101 . 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 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 dosage form after tampering is at least 1.5:1.  
     
     
         102 . The dosage form of  claim 101  wherein said ratio is at least 3:1.  
     
     
         103 . The dosage form of  claim 101  wherein said ratio is at least 4:1.  
     
     
         104 . The dosage form of  claim 101  wherein said ratio is at least 8:1.  
     
     
         105 . The dosage form of  claim 101  wherein said ratio is at least 10:1.  
     
     
         106 . The dosage form of  claim 101  wherein said ratio is at least 50:1.  
     
     
         107 . The dosage form of  claim 101  wherein said ratio is less than about 100:1.  
     
     
         108 . The oral dosage form of  claim 101 , 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.  
     
     
         109 . The oral dosage form of  claim 108 , wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.  
     
     
         110 . The oral dosage form of  claim 101 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         111 . The oral dosage form of  claim 110 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         112 . The oral dosage form of  claim 101 , wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.  
     
     
         113 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 0.75 hours to about 36 hours.  
     
     
         114 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 1 hour to about 30 hours.  
     
     
         115 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 2 hour to about 20 hours  
     
     
         116 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 3 hours to about 20 hours  
     
     
         117 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 5 hours to about 15 hours  
     
     
         118 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 6 hours to about 10 hours  
     
     
         119 . The dosage form of  claim 101 , wherein said antagonist is in the form of multiparticulates individually coated with a material that substantially prevents release of the antagonist.  
     
     
         120 . The dosage form of  claim 101 , wherein said antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.  
     
     
         121 . The dosage form of  claim 101 , wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.  
     
     
         122 . The oral dosage form of  claim 101 , wherein said tampering is by crushing.  
     
     
         123 . The oral dosage form of  claim 101 , wherein said tampering is in a manner as to obtain an immediate release of said agonist.  
     
     
         124 . The oral dosage form of  claim 101 , wherein said tampering is to make the agonist available for inappropriate use.  
     
     
         125 . The oral dosage form of  claim 101 , wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.  
     
     
         126 . 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 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 2:1.  
     
     
         127 . The dosage form of  claim 126  wherein said ratio is at least 4:1.  
     
     
         128 . The dosage form of  claim 126  wherein said ratio is at least 10:1.  
     
     
         129 . The dosage form of  claim 126  wherein said ratio is at least 20:1.  
     
     
         130 . The dosage form of  claim 126  wherein said ratio is at least 50:1.  
     
     
         131 . The dosage form of  claim 126  wherein said ratio is at least 100:1.  
     
     
         132 . The dosage form of  claim 126  wherein said ratio is less than about 150:1.  
     
     
         133 . The oral dosage form of  claim 126 , 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.  
     
     
         134 . The oral dosage form of  claim 133 , wherein the opioid agonist is selected from the group consisting of oxycodone, hydrocodone and pharmaceutically acceptable salts thereof.  
     
     
         135 . The oral dosage form of  claim 126 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         136 . The oral dosage form of  claim 135 , wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, pharmaceutically acceptable salts thereof and mixtures thereof.  
     
     
         137 . The oral dosage form of  claim 126 , wherein the opioid antagonist comprises naltrexone or a pharmaceutically acceptable salt thereof.  
     
     
         138 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 0.75 hours to about 36 hours.  
     
     
         139 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 1 hour to about 30 hours.  
     
     
         140 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 1 hour to about 30 hours pg*h/ml  
     
     
         141 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 2 hours to about 20 hours pg*h/ml  
     
     
         142 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 5 hours to about 15 hours pg*h/ml  
     
     
         143 . The dosage form of  claim 112  wherein the intact dosage form provides a Tmax of naltrexone of about 6 hours to about 10 hours.  
     
     
         144 . The dosage form of  claim 126 , wherein said antagonist is in the form of multiparticulates individually coated with a material that substantially prevents release of the antagonist.  
     
     
         145 . The dosage form of  claim 126 , wherein said antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.  
     
     
         146 . The dosage form of  claim 126 , wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.  
     
     
         147 . The oral dosage form of  claim 126 , wherein said tampering is by crushing.  
     
     
         148 . The oral dosage form of  claim 126 , wherein said tampering is in a manner as to obtain an immediate release of said agonist.  
     
     
         149 . The oral dosage form of  claim 126 , wherein said tampering is to make the agonist available for inappropriate use.  
     
     
         150 . The oral dosage form of  claim 126 , wherein said antagonist does not significantly affect analgesia provided by the agonist when the dosage form is administered intact.  
     
     
         151 . 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 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.  
     
     
         152 . 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 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.  
     
     
         153 . 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 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.  
     
     
         154 . 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 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.  
     
     
         155 . 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 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  
     
     
         156 . 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 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.  
     
     
         157 . A method of treating pain comprising administering a dosage form of  claim 1 .  
     
     
         158 . A method of preparing a dosage form comprising combining an opioid agonist and an opioid antagonist with a pharmaceutically acceptable excipient to form a dosage form of  claim 1 .  
     
     
         159 . A method of preventing abuse of a dosage form comprising preparing a dosage form of claims  1 .