TAMPER RESISTANT DOSAGE FORMS
The present invention relates to pharmaceutical dosage forms, for example to a tamper resistant dosage form including an opioid analgesic, and processes of manufacture, uses, and methods of treatment thereof.
1 - 67 . (canceled)
68 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the formulation comprises:
(1) at least about 80% (by wt) polyethylene oxide (PEO), wherein at least one PEO has an approximate molecular weight of at least 1,000,000 based on rheological measurements; and
(2) oxycodone or a pharmaceutically acceptable salt thereof.
69 . The solid oral extended release pharmaceutical dosage form of claim 68 , wherein the formulation comprises more than about 5% (by wt) of oxycodone hydrochloride.
70 . The solid oral extended release pharmaceutical dosage form of claim 68 , 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.
71 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the formulation comprises:
(1) at least about 80% (by wt) polyethylene oxide (PEO), wherein at least one PEO has an approximate molecular weight of at least 1,000,000 based on rheological measurements; and
(2) 10 mg oxycodone hydrochloride.
72 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the formulation comprises:
(1) at least about 80% (by wt) polyethylene oxide (PEO), wherein at least one PEO has an approximate molecular weight of at least 1,000,000 based on rheological measurements; and
(2) 15 mg oxycodone hydrochloride.
73 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the:
(1) at least about 80% (by wt) polyethylene oxide (PEO), wherein at least one PEO has an approximate molecular weight of at least 1,000,000 based on rheological measurements; and
(2) 20 mg oxycodone hydrochloride.
74 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the formulation comprises:
(1) at least about 80% (by wt) polyethylene oxide (PEO), wherein at least one PEO has an approximate molecular weight of at least 1,000,000 based on rheological measurements; and
(2) 30 mg oxycodone hydrochloride.
75 - 77 . (canceled)
78 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the formulation comprises at least about 80% (by wt) polyethylene oxide and one of oxycodone and a pharmaceutically acceptable salt of oxycodone, wherein:
(2) at least one polyethylene oxide has, based on rheological measurements, has an approximate molecular weight of at least 1,000,000; and
(3) at least one polyethylene oxide has, based on rheological measurements, has an approximate molecular weight of less than 1,000,000.
79 - 83 . (canceled)
84 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the formulation comprises at least about 80% (by wt) polyethylene oxide and one of oxycodone and a pharmaceutically acceptable salt of oxycodone, wherein:
(1) at least one polyethylene oxide has, based on rheological measurements, has an approximate molecular weight of at least 1,000,000; and
(2) the extended release matrix formulation when subjected to an indentation test has a cracking force of at least about 110 N.
85 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, wherein the formulation comprises at least about 80% (by wt) polyethylene oxide and one of oxycodone and a pharmaceutically acceptable salt of oxycodone, wherein:
(1) at least one polyethylene oxide has, based on rheological measurements, has an approximate molecular weight of at least 1,000,000; and
(2) the extended release matrix formulation when subjected to an indentation test has a “penetration depth to crack distance” of at least about 1.0 mm.
86 . The solid oral extended release pharmaceutical dosage form of claim 68 , wherein the extended release dosage form has at least one of (a) a cracking force of at least about 120 N, at least about 130 N or at least about 140 N, and (b) when subjected to an indentation test has a “penetration depth to crack” distance of at least about 1.2 mm, at least about 1.4 mm, at least about 1.5 mm or at least about 1.6 mm.
87 . The solid oral extended release pharmaceutical dosage form of claim 84 , wherein the extended release matrix formulation resists a work of at least about 0.06 J without cracking.
88 - 154 . (canceled)
155 . The extended release dosage form of claim 68 , which is in the form of a tablet formed by direct compression and cured by at least subjecting said tablet to a temperature of at least 60° C. for a time period of at least 15 minutes.
156 . The extended release dosage form of claim 68 , 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.
157 . The extended release dosage form of claim 68 , which is in the form of a stacked bi or multi layered tablet, wherein one of the layers contains the extended release formulation and one of the other layers contains an immediate release formulation.
158 . The extended release dosage form of claim 157 , wherein the immediate release formulation comprises oxycodone or an pharmaceutically acceptable salt of oxycodone.
159 . The extended release dosage form of claim 157 , wherein the immediate release formulation comprises a non opioid analgesic.
160 . A method of treatment wherein a dosage form according to claim 68 , is administered for treatment of pain to a patient in need thereof.
161 . Use of a dosage form according to claim 68 , for the manufacture of a medicament for the treatment of pain.
162 - 169 . (canceled)
170 . A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation in a tablet or multi-particulate structure, wherein the formulation comprises oxycodone or a pharmaceutically acceptable salt of oxycodone and at least about 60% (by wt) polyethylene oxide (PEO), and wherein at least one PEO is a high molecular weight PEO having an approximate molecular weight of at least 1,000,000 based on rheological measurements.
171 . The dosage form according to claim 170 , further comprising at least one low molecular weight PEO having an approximate molecular weight of less than 1,000,000 based on rheological measurements.
172 . (canceled)
173 . The dosage form of claim 170 , wherein at least one high molecular weight PEO has an approximate molecular weight, based on rheological measurements, selected from 4,000,000 and 7,000,000.
174 . The dosage form of claim 170 , wherein at least one high molecular weight PEO has an approximate molecular weight of 7,000,000 based on rheological measurements.
175 - 178 . (canceled)
179 . The dosage form according to claim 171 , wherein the high molecular weight PEO and low molecular weight PEO together comprise at least about 80% (by wt) of the formulation.
180 . The dosage form according to claim 171 , wherein the high molecular weight PEO comprises at least about 80% (by wt) of the formulation.
181 . The dosage form according to claim 170 , wherein the formulation comprises oxycodone hydrochloride.
182 . The dosage form according to claim 171 , wherein the formulation comprises oxycodone hydrochloride.
183 . The dosage form according to claim 181 , wherein the formulation comprises more than about 5% (by wt) of oxycodone hydrochloride.
184 . The dosage form according to claim 182 , wherein the formulation comprises more than about 5% (by wt) of oxycodone hydrochloride.
185 . The dosage form of claim 181 , wherein at least one high molecular weight PEO has an approximate molecular weight of 4,000,000 based on rheological measurements.
186 . The dosage form of claim 182 , wherein at least one high molecular weight PEO has an approximate molecular weight of 7,000,000 based on rheological measurements.
187 . The dosage form of claim 183 , wherein at least one high molecular weight PEO has an approximate molecular weight of 4,000,000 based on rheological measurements.
188 . The dosage form of claim 184 , wherein at least one high molecular weight PEO has an approximate molecular weight of 7,000,000 based on rheological measurements.
189 . The dosage form of claim 170 that is resistant to crushing, and can at least be flattened without breaking to no more than about 60% of the thickness of the tablet or individual multi-particulate before flattening, wherein the flattened tablets or multi particulates provide an in-vitro dissolution rate, when measured in simulated gastric fluid without enzymes (SGF) at 37° C., such that the percent amount of oxycodone or its pharmaceutically acceptable salt released at 0.5 hours of dissolution deviates no more than about 20% from the corresponding in-vitro dissolution rate of a non-flattened reference tablet or multi particulate.
190 . The dosage form of claim 170 that is resistant to alcohol extraction or dose dumping, wherein the tablets or multi particulates provide an in-vitro dissolution rate, when measured in simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C., such that the percent amount of oxycodone or its pharmaceutically acceptable salt released at 0.5 hours or 1 hour of dissolution deviates no more than about 20% from the corresponding in-vitro dissolution rate of a reference tablet or multi particulate under the same conditions, without ethanol.
191 . The dosage form of claim 189 that is resistant to alcohol extraction or dose dumping, wherein the non-flattened tablets or multi particulates provide an in-vitro dissolution rate, when measured in simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C., such that the percent amount of oxycodone or its pharmaceutically acceptable salt released at 0.5 hours or one hour of dissolution deviates no more than about 20% from the corresponding in-vitro dissolution rate of a non-flattened reference tablet or multi particulate under the same conditions, without ethanol.
192 . The dosage form of claim 189 that is resistant to alcohol extraction or dose dumping, wherein the flattened tablets or multi particulates provide an in-vitro dissolution rate, when measured in simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C., such that the percent amount of oxycodone or its pharmaceutically acceptable salt released at 0.5 hours or one hour of dissolution deviates no more than about 20% from the corresponding in-vitro dissolution rate of a flattened reference tablet or multi particulate under the same conditions, without ethanol.
193 . The dosage form of claim 189 that is resistant to alcohol extraction or dose dumping, wherein the flattened tablets or multi particulates provide an in-vitro dissolution rate, when measured in simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C., such that the percent amount of oxycodone or its pharmaceutically acceptable salt released at 0.5 hours or one hour of dissolution deviates no more than about 20% from the corresponding in-vitro dissolution rate of a non-flattened reference tablet or multi particulate under the same conditions, without ethanol.
194 . The dosage form of claim 190 , wherein about 5-40% of the oxycodone or a pharmaceutically acceptable salt thereof is released within 0.5 hours, with or without alcohol.
195 . The dosage form of claim 190 , wherein about 5-40% of the oxycodone or a pharmaceutically acceptable salt thereof is released within 1 hour, with or without alcohol.
196 . The dosage form according to claim 180 , wherein the formulation comprises at least about 85% (by wt) PEO.
197 . The dosage form according to claim 180 , wherein the formulation comprises at least about 90% (by wt) PEO.
198 . The dosage form according to claim 190 , wherein the percent amount of oxycodone or its pharmaceutically acceptable salt released at 0.5 hours or one hour of dissolution deviates no more than about 15% from the corresponding in-vitro dissolution rate of the reference tablet or multi particulate.
199 . The dosage form of claim 194 , wherein the percent of the oxycodone or its pharmaceutically acceptable salt that is released within 0.5 hours or one hour is within a range selected from about 5-30%, about 5-20%, or about 10-18%.
200 . The dosage form of claim 195 , wherein the percent of the oxycodone or its pharmaceutically acceptable salt this is released with 1 hour is within a range selected from about 5-30%, about 5-20%, or about 10-18%.
201 . The dosage form according to claim 181 , comprising one of about 10 mg, 15 mg, 20 mg, or 30 mg oxycodone hydrochloride.
202 . The dosage form according to claim 199 , comprising one of about 10 mg, 15 mg, 20 mg, or 30 mg oxycodone hydrochloride.
203 . The dosage form according to claim 200 , comprising one of about 10 mg, 15 mg, 20 mg, or 30 mg oxycodone hydrochloride.
204 . The dosage form according to claim 190 , wherein dissolution is measured using one of: (a) a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF); or (b) a USP Apparatus 2 (paddle) at 50 or 75 rpm in 500 ml or 900 ml simulated gastric fluid without enzymes (SGF).
205 . The dosage form according to claim 170 , wherein
(1) at least one PEO is a high molecular weight PEO having an approximate molecular weight of at least 1,000,000 based on rheological measurements; and
(2) the formulation is cured at a temperature which is at least as high as the lower limit of the softening temperature of the high molecular weight PEO, such that the PEO at least partially melts.
206 . The dosage form according to claim 205 , wherein curing is conducted at atmospheric pressure.
207 . (canceled)
208 . The dosage form according to claim 205 , wherein curing is conducted for at least 5 minutes.
209 . The dosage form according to claim 205 , wherein curing is conducted at an effective curing temperature within the range of about 60-90° C. for at least 5 minutes.
210 - 211 . (canceled)
212 . The dosage form according to claim 205 , wherein curing is conducted at an effective curing temperature within the range of about 62-72° C. for at least 5 minutes.
213 . The dosage form according to claim 209 , wherein the curing time is in the range of from about 30 minutes to about 4 hours.
214 - 219 . (canceled)
220 . The dosage form according to claim 209 , wherein the curing time is in the range of from about 15 minutes to 2 hours.
221 . The dosage form according to claim 209 , wherein the curing time is in the range of from about 15 minutes to about 1 hour.
222 . The dosage form according to claim 170 , wherein the formulation has a density of less than about 1.20 g/cm 3 .