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:

(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and

(2) at least one active agent selected from opioid analgesics wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from 5 mg to 500 mg of oxycodone hydrochloride; and

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.

171 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the opioid analgesic is oxycodone hydrochloride and the composition comprises more than 5% (by wt) of the oxycodone hydrochloride.

172 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the composition comprises 10 mg oxycodone hydrochloride, and at least about 85% (by wt) polyethylene oxide.

173 . The solid oral extended release pharmaceutical dosage form of claim 170 , wherein the composition comprises 15 mg or 20 mg oxycodone hydrochloride.

174 . 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/cm 3 or equal to or less than about 1.19 g/cm 3 .

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 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.

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 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.

178 . The solid oral extended release pharmaceutical dosage form of claim 177 , wherein the extended release matrix formulation has been stored at 40° C. and 75% relative humidity (RH).

179 . 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.

180 . 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™.

181 . 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; and

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.

182 . The extended release dosage form of claim 170 , 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.

183 . 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, of less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.

184 . The extended release dosage form of claim 181 , wherein the opioid analgesic is oxycodone hydrochloride having a 14-hydroxycodeinone level of less than about 25 ppm, of less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.

185 . 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.

186 . The extended release dosage form of claim 181 , 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.

187 . 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.

188 . 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.

189 . The extended release dosage form of claim 188 , wherein the extended release formulation and the immediate release formulation contain the same or different active agents.

190 . The extended release dosage form of claim 188 , wherein the extended release formulation comprises an opioid analgesic and the immediate release formulation comprises a non opioid analgesic.

191 . A method of treatment wherein a dosage form according to claim 170 is administered for the treatment of pain to a patient in need thereof, wherein the dosage form comprises oxycodone hydrochloride.

192 . A pharmaceutical tablet in accordance with 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.

193 . A pharmaceutical tablet in accordance with claim 181 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.

194 . A pharmaceutical tablet in accordance with 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.

195 . A pharmaceutical tablet in accordance with claim 181 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.

196 . A pharmaceutical tablet in accordance with claim 170 capable of resisting a work of at least 0.06 J without cracking.

197 . A pharmaceutical tablet in accordance with claim 181 capable of resisting a work of at least 0.06 J without cracking.

198 . A pharmaceutical tablet in accordance with claim 170 having (a) 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; (b) 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; and (c) capable of resisting a work of at least 0.06 J without cracking.

199 . The pharmaceutical tablet in accordance with claim 192 having a density of less than 1.20 g/cm 3 or less than 1.19 g/cm 3 .