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. A pharmaceutical composition comprising:
at least one active agent;
at least one high molecular weight polyethylene oxide (PEO) having an approximate molecular weight of from 1 million to 15 million;
optionally at least one additive;
optionally at least one film coating; and
optionally at least one low molecular weight PEO having an approximate molecular weight of less than 1,000,000; wherein
(a) the active agent and high molecular weight PEO are combined in a solid oral extended release dosage form that is (i) compression shaped, (ii) air cured by heated air, without compression, for at least about 5 minutes at a temperature above the softening temperature of the high molecular weight PEO, (iii) cooled, and (iv) hardened;
(b) the high molecular weight PEO comprises at least about 30% (by weight) of the dosage form;
(c) the molecular weight of each PEO is based on rheological measurements; and
(d) the total weight of the dosage form is calculated by excluding the combined weight of said film coatings.
2. A pharmaceutical composition according to claim 1 , wherein the high molecular weight PEO is at least partially melted upon curing.
3. A pharmaceutical composition according to claim 1 , wherein the curing temperature is from about 70° C. to about 85° C. and the curing time is from about 10 minutes to about 10 hours.
4. A pharmaceutical composition according to claim 1 , wherein the curing temperature is at least about 60° C. and the curing time is at least about 10 minutes.
5. A pharmaceutical composition according to claim 4 , wherein the curing temperature does not exceed about 90° C. and the curing time does not exceed about 24 hours.
6. A pharmaceutical composition according to claim 5 , wherein the curing time does not exceed about 10 hours.
7. A pharmaceutical composition according to claim 6 , wherein the active agent comprises at least about 1.3% of the dosage form and the dosage form comprises a tablet.
8. A pharmaceutical composition according to claim 7 , wherein the low molecular weight PEO is present and has an approximate molecular weight of from 100,000 to 900,000.
9. A pharmaceutical composition according to claim 7 , wherein the dosage form is expanded upon curing, as measured by a decrease in density of at least about 1%, and the dosage form provides a hardness of at least about 439 N.
10. A pharmaceutical composition according to claim 9 , wherein at least one film coating is present; at least one additive is present; and the additive is selected from at least one of an anti-tacking agent, an antioxidant, an immediate release component, and a retardant.
11. A pharmaceutical composition comprising:
at least one active agent comprising an opioid or a pharmaceutically acceptable salt thereof;
at least one high molecular weight polyethylene oxide (PEO) having an approximate molecular weight of from 1 million to 8 million;
at least one additive comprising an anti-tacking agent, an antioxidant, an immediate release component, or a retardant;
optionally a film coating; and
optionally at least one low molecular weight PEO having an approximate molecular weight of less than 1,000,000; wherein
(a) the active agent and high molecular weight PEO are combined in a solid oral extended release dosage form that is (i) compression shaped, (ii) air cured by heated air, without compression, for a curing time of at least about 10 minutes at a curing temperature of at least about 60° C., (iii) cooled, and (iv) hardened;
(b) the high molecular weight PEO comprises at least about 30% (by weight) of the dosage form;
(c) the active agent comprises at least about 1.3% (by weight) of the dosage form;
(d) the molecular weight of each PEO is based on rheological measurements; and
(e) the total weight of the dosage form is calculated by excluding the combined weight of said film coatings.
12. A pharmaceutical composition according to claim 11 ,
wherein the dosage form is a tablet;
at least one additive comprises an anti-tacking agent;
the compression shaped tablet is cured and cooled in a convection curing device provided with inlet air, exhaust air, and a bed of free flowing tablets;
the tablet is cured by air having a curing temperature of about 60° C. to about 90° C., for a curing time of about 10 minutes to about 10 hours, and is cooled by air having a cooling temperature below about 50° C.; and
each of the curing temperature and the cooling temperature is one of (a) the temperature of the inlet air, or (b) the temperature of the exhaust air.
13. A pharmaceutical composition according to claim 12 , wherein the tablet is expanded upon curing, as measured by a decrease in tablet density of at least about 1%.
14. A pharmaceutical composition according to claim 12 , wherein the active agent (i) is selected from the group consisting of buprenorphine, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, and pharmaceutically acceptable salts thereof, and (ii) is at least about 2.4% (by weight) of each tablet.
15. A pharmaceutical composition according to claim 12 , wherein the curing temperature is from about 70° C. to about 85° C. and the high molecular weight PEO has an approximate molecular weight that is selected from at least one of 1 million, 2 million, 4 million, 5 million, and 7 million.
16. A pharmaceutical composition according to claim 12 , wherein the total of high and low molecular weight PEO comprises at least about 65% (by weight) of the dosage form.
17. A pharmaceutical composition according to claim 12 , wherein the total of high and low molecular weight PEO comprises at least about 80% (by weight) of the dosage form.
18. A pharmaceutical composition according to claim 12 , wherein the low molecular weight PEO is present and has an approximate molecular weight of from 100,000 to 900,000.
19. A pharmaceutical composition according to claim 12 , wherein at least one additive is selected from butylated hydroxytoluene (BHT), magnesium stearate, talc, silica, fumed silica, colloidal silica dioxide, calcium stearate, carnauba wax, stearic acid, stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose, glycerin, propylene glycol, polyethylene glycol, lactose, povidone, triacetin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and copolymers comprising methyl methacrylate.
20. A pharmaceutical composition according to claim 12 , wherein the total of high and low molecular weight PEO comprises at least about 50% (by weight) of the dosage form.
21. A pharmaceutical composition according to claim 20 , wherein the high molecular weight PEO has an approximate molecular weight selected from 4 million and 7 million.
22. A pharmaceutical composition according to claim 12 , wherein the convection curing device is a coating pan and the curing temperature and cooling temperature are each the exhaust temperature of the coating pan.
23. A pharmaceutical composition according to claim 22 , wherein the curing temperature has a plateau-like temperature profile.
24. A pharmaceutical composition according to claim 22 , wherein the cooling temperature is from about 30° C. to about 34° C.
25. A pharmaceutical composition according to claim 12 , wherein the tablet is expanded upon curing, as measured by a decrease in tablet density of at least about 2%.
26. A pharmaceutical composition according to claim 25 , wherein the total of high and low molecular weight PEO comprises at least about 65% (by weight) of the dosage form.
27. A pharmaceutical composition according to claim 25 , wherein the total of high and low molecular weight PEO comprises at least about 90% (by weight) of the dosage form.
28. A pharmaceutical composition according to claim 25 , wherein the low molecular weight PEO is present and has an approximate molecular weight of from 100,000 to 900,000.
29. A pharmaceutical composition according to claim 25 , wherein the total of high and low molecular weight PEO comprises at least about 50% (by weight) of the dosage form.
30. A pharmaceutical composition according to claim 29 , wherein the high molecular weight PEO has an approximate molecular weight selected from 4 million and 7 million.