Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia
View Patent ↗The present disclosure provides an extended release pharmaceutical composition comprising hydrocodone and acetaminophen that provides a rapid onset of analgesia, and reduced levels of acetaminophen near the end of the dosing interval. Also provided are methods for reducing the risk of acetaminophen-induced hepatic damage in a subject being treated with an acetaminophen containing composition, as well as methods for treating pain in a subject in need thereof.
1. A pharmaceutical composition for extended release of hydrocodone and acetaminophen, comprising:
at least one extended release portion comprising hydrocodone or a pharmaceutically acceptable salt thereof, acetaminophen, and an extended release component;
wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or salt in the composition is about 7.5 mg to about 15 mg; and
wherein composition provides an AUC 0-1.27h for acetaminophen of about 3 ng·h/mL/mg to about 13 ng·h/mL/mg; an AUC 1.27-36h for acetaminophen of about 20 ng·h/mL/mg to about 75 ng·h/mL/mg; an AUC 0-2.4h for hydrocodone or salt of about 0.5 ng·h/mL/mg to about 5 ng·h/mL/mg; and AUC 2.4-36h for hydrocodone or salt of about 5 ng·h/mL/mg to about 25 ng·h/mL/mg.
2. The pharmaceutical composition of claim 1 , wherein the AUC 0-1.27h for acetaminophen is about 5 ng·h/mL/mg to about 10 ng·h/mL/mg.
3. The pharmaceutical composition of claim 1 , wherein the AUC 1.27-36h for acetaminophen is about 30 ng·h/mL/mg to about 50 ng·h/mL/mg.
4. The pharmaceutical composition of claim 1 , wherein the AUC 0-24h for hydrocodone or salt is about 1.5 ng·h/mL/mg to about 3 ng·h/mL/mg.
5. The pharmaceutical composition of claim 1 , wherein the AUC 2.4-36h for hydrocodone or salt is about 13 ng·h/mL/mg to about 17 ng·h/mL/mg.
6. The pharmaceutical composition of claim 1 , wherein the composition comprises about 650 mg of acetaminophen and about 15 mg of hydrocodone or salt.
7. The pharmaceutical composition of claim 1 , wherein the composition comprises about 325 mg of acetaminophen and about 7.5 mg of hydrocodone or salt.
8. The pharmaceutical composition of claim 7 , wherein the composition is in the form of a tablet and a single dose comprises two tablets.
9. The pharmaceutical composition of claim 1 , wherein the extended release component comprises at least one extended release polymer.
10. The pharmaceutical composition of claim 9 , wherein the at least one extended release polymer is a polyethylene oxide.
11. The pharmaceutical composition of claim 10 , wherein the molecular weight of the polyethylene oxide is from about 500,000 Daltons to about 10,000,000 Daltons.
12. The pharmaceutical composition of claim 1 , wherein the composition further comprises at least one immediate release portion comprising hydrocodone or a pharmaceutically acceptable salt thereof, acetaminophen, or a combination thereof.
13. The pharmaceutical composition of claim 12 , wherein the at least one immediate release portion comprises from about 20% to about 30% of the total amount of hydrocodone or salt in the composition and from about 40% to about 60% of the total amount of acetaminophen in the composition; and the at least one extended release portion comprises the balance of each of the hydrocodone or salt and the acetaminophen.
14. The pharmaceutical composition of claim 12 , wherein the composition comprises (a) one immediate release portion comprising the hydrocodone or salt and the acetaminophen, and (b) one extended release portion comprising the extended release polymer, the hydrocodone or salt and the acetaminophen.
15. The pharmaceutical composition of claim 14 , wherein the immediate release portion comprises, by weight of the immediate release portion, from about 70% to about 80% acetaminophen and from about 0.5% to about 1% of hydrocodone or salt; and the extended release portion comprises, by weight of the extended release portion, from about 30% to about 50% of the extended release polymer, from about 20% to about 40% of acetaminophen, and from about 0.5% to about 2% of hydrocodone or salt.
16. A therapeutically effective pharmaceutical composition for oral administration in the treatment of pain, comprising:
at least one extended release portion comprising hydrocodone or a pharmaceutically acceptable salt thereof, acetaminophen, and an extended release component;
wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or salt in the composition is about 7.5 mg to about 15 mg;
wherein when the composition is orally administered to a subject in need thereof, the subject attains therapeutic blood levels of both the hydrocodone and the acetaminophen within about one hour after administration of the composition and maintains analgesia for about 12 hours after administration of the composition; and
wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 100 rpm in 900 ml of 0.1N HCl using a USP type II apparatus at a constant temperature of 37° C., the drug release profile substantially corresponds to the following:
after 2 hours, no more than about 65%, by weight, of the total amount of the hydrocodone or salt is released and no more than about 80%, by weight, of the total amount of the acetaminophen is released;
after 4 hours, from about 65% to about 85%, by weight, of the total amount of the hydrocodone or salt is released and from about 65% to about 95%, by weight, of the total amount of the acetaminophen is released;
after 8 hours, from about 80% to about 100%, by weight, of the total amount of the hydrocodone or salt is released and from about 80% to about 100%, by weight, of the total amount of the acetaminophen is released; and
after 12 hours, from about 85% to about 100%, by weight, of the total amount of the hydrocodone or salt is released and from about 85% to about 100%, by weight, of the total amount of the acetaminophen is released.
17. The pharmaceutical composition of claim 16 wherein upon oral administration of the composition in an amount of about 15 mg hydrocodone or salt and about 650 mg acetaminophen, the composition maintains a therapeutic plasma concentration of hydrocodone of at least about 5 ng/mL from about 0.75 hour to about 10 hours after administration of the composition, and wherein at least about 90% of the acetaminophen is released from the composition by about 8 hours after administration of the composition such that, by about 10 hours after administration of the composition, acetaminophen has a blood plasma concentration that is less than about 30% of acetaminophen's maximum plasma concentration.
18. The pharmaceutical composition of claim 16 , wherein the extended release portion comprises at least one extended release polymer.
19. A pharmaceutical composition comprising:
at least one immediate release portion comprising hydrocodone or a pharmaceutically acceptable salt thereof and acetaminophen and at least one extended release portion comprising an extended release component, hydrocodone or a pharmaceutically acceptable salt thereof, and acetaminophen;
wherein the at least one immediate release portion comprises from about 20% to about 30% (w/w) of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof, and about 40% to about 60% (w/w) of the total amount of the acetaminophen in the composition;
wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or salt in the composition is about 7.5 mg to about 15 mg;
wherein upon oral administration, the composition maintains a therapeutic blood plasma concentration of hydrocodone of at least 5 ng/mL from about 0.75 hours to about 10 hours after administration of the composition, and wherein at least about 90% of the acetaminophen is released from the composition by about 8 hours after administration of the composition such that, by about 10 hours after administration of the composition, acetaminophen has a blood plasma concentration that is less than about 30% of acetaminophen's maximum plasma concentration.
20. The pharmaceutical composition of claim 19 , wherein depleted stores of hepatic glutathione are able to be substantially replenished to pre-dose levels of glutathione during at least the last two hours of a 12-hour dosing interval when plasma concentrations of acetaminophen are reduced.
21. The pharmaceutical composition of claim 19 , wherein the composition achieves a Cmax comparable to an immediate-release acetaminophen product with a 6-hour dosing interval.
22. The pharmaceutical composition of claim 19 , wherein the acetaminophen released from the composition is eliminated by a subject's body faster than the acetaminophen is being absorbed by the subject's body.