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 solid, oral, extended release pharmaceutical tablet comprising:
(A) a core comprising:
a therapeutically effective amount of a hydrochloride salt of an opioid analgesic;
an antioxidant;
hydroxypropyl methylcellulose;
polyethylene glycol;
at least one hardened high molecular weight polyethylene oxide (PEO), wherein said high molecular weight PEO has an approximate molecular weight of from 4 million to 8 million, based upon rheological measurements, and is present in an amount of at least about 30% (by weight) of the core;
(B) a coating on said core, said coating comprising:
a. polyethylene glycol;
b. talc; and
c. titanium dioxide;
wherein said tablet
is crush resistant and has a breaking strength of at least about 439 N;
is resistant to alcohol extraction and has an in vitro dissolution rate of said opioid hydrochloride salt, at 0.5 hours in simulated gastric fluid with 40% ethanol, that differs by no more than about 20% points from a corresponding in vitro dissolution rate without ethanol; and
provides a mean t max of said opioid hydrochloride salt at about 2 to about 6 hours after administration of a single tablet in a human subject.
2. A tablet according to claim 1 , wherein the opioid hydrochloride salt comprises at least about 1.3% (by weight) of the core.
3. A tablet according to claim 2 , wherein the opioid hydrochloride salt comprises at least about 2.4% (by weight) of the core.
4. A tablet according to claim 2 , wherein the opioid hydrochloride salt comprises at least about 5% (by weight) of the core.
5. A tablet according to claim 1 , wherein
after storage at 40° C., 75% relative humidity in a closed 100 count bottle for 3 months, said tablet releases at least 95% of the amount of opioid hydrochloride salt in said tablet before such storage, as determined by stirring and dissolution in a medium comprising simulated gastric fluid for 12 hours; and
after storage at 25° C., 60% relative humidity in a closed 100 count bottle for 6 months, releases at least 95% of the amount of opioid hydrochloride salt in said tablet before such storage, as determined by stirring and dissolution in a medium comprising simulated gastric fluid for 12 hours.
6. A tablet according to claim 5 , wherein the opioid hydrochloride salt comprises at least about 5% (by weight) of said core, the dosage amount of opioid hydrochloride salt is about 5 mg to about 500 mg, the antioxidant is Vitamin E, and the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
7. A tablet according to claim 5 , wherein the opioid hydrochloride salt comprises at least about 5% (by weight) of said core and said high molecular weight PEO comprises at least about 50% (by weight) of said core.
8. A tablet according to claim 7 , wherein the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
9. A tablet according to claim 8 , wherein the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
10. A tablet according to claim 1 , wherein
(i) when said tablet is flattened without breaking to no more than about 60% of its thickness before flattening, said flattened tablet has an in-vitro dissolution, when measured in a USP Apparatus 1 (basket) at 100 rpm and at 37° C. in 900 ml of simulated gastric fluid having no enzymes and having 40% ethanol, wherein the percent amount of said opioid hydrochloride salt released at 0.5 hours of dissolution deviates no more than about 15% from the corresponding in-vitro dissolution without ethanol;
(ii) between 5 and 40% of said opioid hydrochloride salt (by weight) in said tablet is released after 0.5 hours, when measured in a USP Apparatus 1 (basket) at 100 rpm and at 37° C. in 900 ml of simulated gastric fluid having no enzymes and having 40% or 0% ethanol; or
(iii) a combination of (i) and (ii).
11. A tablet according to claim 10 , wherein the opioid hydrochloride salt comprises at least about 5% (by weight) of said core and said high molecular weight PEO comprises at least about 50% (by weight) of said core.
12. A tablet according to claim 10 , wherein the opioid hydrochloride salt comprises at least about 5% (by weight) of said core, the dosage amount of opioid hydrochloride salt is about 5 mg to about 500 mg, the antioxidant is Vitamin E, and the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
13. A tablet according to claim 1 , wherein the molecular weight of said high molecular weight PEO is at least one of 4 million, 5 million, 7 million, and 8 million.
14. A tablet according to claim 1 , wherein the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
15. A tablet according to claim 1 , wherein said high molecular weight PEO comprises at least about 50% (by weight) of said core.
16. A tablet according to claim 15 , wherein the antioxidant is Vitamin E and the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
17. A tablet according to claim 15 , wherein the dosage amount of opioid hydrochloride salt is about 5 mg to about 500 mg.
18. A tablet according to claim 17 that is suitable for twice-daily administration to a human patient in need of analgesic treatment.
19. A tablet according to claim 15 , wherein said high molecular weight PEO comprises at least about 65% (by weight) of the core.
20. A tablet according to claim 19 , wherein said high molecular weight PEO comprises at least about 80% (by weight) of the core.
21. A tablet according to claim 20 , wherein said high molecular weight PEO comprises at least about 90% (by weight) of the core.
22. A tablet according to claim 21 , wherein the antioxidant is Vitamin E and the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
23. A tablet according to claim 20 , wherein the antioxidant is Vitamin E and the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
24. A tablet according to claim 19 , wherein the antioxidant is Vitamin E and the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
25. A tablet according to claim 1 , wherein the opioid hydrochloride salt comprises at least about 5% (by weight) of said core, the dosage amount of opioid hydrochloride salt is about 5 mg to about 500 mg, the antioxidant is Vitamin E, and the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
26. A solid, oral, extended release pharmaceutical tablet comprising:
(A) a core consisting of:
a. a therapeutically effective amount of a hydrochloride salt of an opioid analgesic;
b. vitamin E;
c. hydroxypropyl methylcellulose;
d. polyethylene glycol;
e. at least one high molecular weight polyethylene oxide (PEO) that is hardened by exposure to a temperature of at least 60° C., wherein said high molecular weight PEO has an approximate molecular weight of from 4 million to 8 million, based upon rheological measurements, and is present in an amount of at least about 30% (by weight) of the core;
(B) a coating on said core, said coating comprising:
a. polyethylene glycol;
b. talc; and
c. titanium dioxide;
wherein said tablet
is crush resistant and has a breaking strength of at least about 439 N;
is resistant to alcohol extraction and has an in vitro dissolution rate of said opioid hydrochloride salt, at 0.5 hours in simulated gastric fluid with 40% ethanol, that differs by no more than about 20% points from a corresponding in vitro dissolution rate without ethanol; and
provides a mean t max of said opioid hydrochloride salt at about 2 to about 6 hours after administration of a single tablet in a human subject.
27. A tablet according to claim 26 , wherein the molecular weight of said high molecular weight PEO is at least one of 4 million and 7 million.
28. A tablet according to claim 27 , wherein the opioid hydrochloride salt comprises at least about 5% (by weight) of the core.
29. A tablet according to claim 28 , wherein said high molecular weight PEO comprises at least about 50% (by weight) of said core.
30. A tablet according to claim 28 , wherein the dosage amount of opioid hydrochloride salt is about 5 mg to about 500 mg, and the tablet is suitable for twice-daily administration to a human patient in need of analgesic treatment.