TAMPER RESISTANT DOSAGE FORMS

1 - 169 . (canceled)

170 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least one active agent and at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; wherein the extended release matrix formulation is cured at a temperature of at least about 60° C. for a time period of at least about 1 minute, in the form of a tablet or multi particulates, wherein the tablet or the individual multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 60% of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the flattened or non flattened multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C., characterized by the percent amount of active agent released at 0.5 hours of dissolution that deviates no more than about 20% points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C. without ethanol, using a flattened and non flattened reference tablet or flattened and non flattened reference multi particulates, respectively.

171 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the tablet or the multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 60%, or no more than about 50%, or no more than about 40%, or no more than about 30%, or no more than about 20%, or no more than about 16% of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the individual multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C., characterized by the percent amount of active agent released at 0.5 hours of dissolution that deviates no more than about 20% points or no more than about 15% points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C. without ethanol, using a flattened and a non flattened reference tablet or reference multi particulates, respectively.

172 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the density of the extended release matrix formulation is equal to or less than about 1.20 g/cm3, or is equal to or less than about 1.19 g/cm3.

173 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the extended release matrix formulation after having been stored at 25° C. and 60% relative humidity (RH) for at least 1 month provides a dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C., characterized by the percent amount of active agent released at 1, 4 and 12 hours of dissolution that deviates no more than about 15% points from the corresponding in-vitro dissolution rate of a reference formulation prior to storage.

174 . The solid oral extended release pharmaceutical dosage form of claim 173 , wherein the extended release matrix formulation has been stored at 40° C. and 75% relative humidity (RH).

175 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the extended release matrix formulation after having been stored at 25° C. and 60% relative humidity (RH) for at least 1 month contains an amount of the at least one active agent in % (by wt) relative to the label claim of the active agent for the extended release matrix formulation that deviates no more than about 10% points from the corresponding amount of active agent in % (by wt) relative to the label claim of the active agent for the extended release matrix formulation of a reference formulation prior to storage.

176 . The solid oral extended release pharmaceutical dosage form of claim 175 , wherein the extended release matrix formulation has been stored at 40° C. and 75% relative humidity (RH).

177 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the dosage form provides a dissolution rate, which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C., is between 12.5 and 55% (by wt) active released after 1 hour, between 25 and 65% (by wt) active released after 2 hours, between 45 and 85% (by wt) active released after 4 hours and between 55 and 95% (by wt) active released after 6 hours.

178 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the active agent is oxycodone hydrochloride and wherein the dosage form when tested in a comparative clinical study is bioequivalent to the commercial product OxyContin™.

179 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the active agent is oxycodone hydrochloride and wherein a dosage form comprising 10 mg of oxycodone hydrochloride when tested in a comparative clinical study is bioequivalent to a reference tablet containing 10 mg of oxycodone hydrochloride in a matrix formulation containing:

a) Oxycodone hydrochloride: 10.0 mg/tablet

b) Lactose (spray-dried): 69.25 mg/tablet

c) Povidone: 5.0 mg/tablet

d) Eudragit® RS 30D (solids): 10.0 mg/tablet

e) Triacetin®: 2.0 mg/tablet

f) Stearyl alcohol: 25.0 mg/tablet

g) Talc: 2.5 mg/tablet

h) Magnesium Stearate: 1.25 mg/tablet;

and wherein the reference tablet is prepared by the following steps:

1. Eudragit® RS 30D and Triacetin® are combined while passing through a 60 mesh screen, and mixed under low shear for approximately 5 minutes or until a uniform dispersion is observed,

2. Oxycodone HCl, lactose, and povidone are placed into a fluid bed granulator/dryer (FBD) bowl, and the suspension sprayed onto the powder in the fluid bed,

3. after spraying, the granulation is passed through a #12 screen if necessary to reduce lumps,

4. the dry granulation is placed in a mixer,

5. in the meantime, the required amount of stearyl alcohol is melted at a temperature of approximately 70° C.,

6. the melted stearyl alcohol is incorporated into the granulation while mixing,

7. the waxed granulation is transferred to a fluid bed granulator/dryer or trays and allowed to cool to room temperature or below,

8. the cooled granulation is then passed through a #12 screen,

9. the waxed granulation is placed in a mixer/blender and lubricated with the required amounts of talc and magnesium stearate for approximately 3 minutes, and

10. the granulate is compressed into 125 mg tablets on a suitable tableting machine.

180 . The extended release dosage form of claim 170 , wherein the composition comprises at least about 80% (by wt) of polyethylene oxide.

181 . The extended release dosage form of claim 180 , wherein the composition comprises at least about 80% (by wt) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.

182 . The extended release dosage form of claim 170 , wherein the active agent is an opioid analgesic.

183 . The extended release dosage form of claim 182 , wherein the opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.

184 . The extended release dosage form of claim 182 , wherein the opioid analgesic is selected from the group consisting of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.

185 . The extended release dosage form of claim 170 , wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from about 5 mg to about 500 mg of oxycodone hydrochloride.

186 . The extended release dosage form of claim 185 , wherein the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, 80 mg, 90 mg, 120 mg, or 160 mg of oxycodone hydrochloride.

187 . The extended release dosage form of claim 170 , wherein the opioid analgesic is oxycodone hydrochloride having a 14-hydroxycodeinone level of less than about 25 ppm, less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.

188 . The extended release dosage form of claim 182 , wherein the opioid analgesic is oxymorphone hydrochloride and the dosage form comprises from about 1 mg to about 500 mg of oxymorphone hydrochloride.

189 . The extended release dosage form of claim 188 , wherein the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, 80 mg, 90 mg, 120 mg, or 160 mg of oxymorphone hydrochloride.

190 . The extended release dosage form of claim 182 , wherein the opioid analgesic is hydromorphone hydrochloride and the dosage form comprises from about 1 mg to about 100 mg of hydromorphone hydrochloride

191 . The extended release dosage form of claim 190 , wherein the dosage form comprises 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg, or 64 mg of hydromorphone hydrochloride.

192 . The extended release dosage form of claim 170 , which is in the form of a tablet formed by direct compression of the composition and cured by at least subjecting said tablet to a temperature of at least about 60° C. or at least about 62° C. for a time period of at least about 1 minute, at least about 5 minutes, or at least about 15 minutes.

193 . The extended release dosage form of claim 170 , which is in the form of a tablet and which is over coated with a polyethylene oxide powder layer to form a tablet that has a core tablet and a layer of polyethylene oxide surrounding the core tablet.

194 . The extended release dosage form of claim 170 , which is in the form of a stacked bi or multi layered tablet, wherein one of the layers contains an extended release formulation and one of the other layers contains an immediate release formulation.

195 . The extended release dosage form of claim 194 , wherein the extended release formulation and the immediate release formulation contain the same or different active agents.

196 . The extended release dosage form of claim 194 , wherein the extended release formulation comprises an opioid analgesic and the immediate release formulation comprises a non opioid analgesic.

197 . A pharmaceutical tablet according to claim 170 , having a cracking force of at least 110 N, at least 120 N, at least 130 N, or at least 140 N, when subjected to an indentation test.

198 . A pharmaceutical tablet according to claim 170 , having a penetration depth to crack distance of at least 1.0 mm, at least 1.2 mm, at least 1.4 mm, or at least 1.6 mm, when subjected to an indentation test.

199 . A pharmaceutical tablet according to claim 170 , capable of resisting a work of at least 0.06 J without cracking