Claims for Patent: 9,468,636

Summary for Patent: 9,468,636

Title:	Combination composition comprising oxycodone and acetaminophen for rapid onset and extended duration of analgesia
Abstract:	The present disclosure provides an extended release pharmaceutical composition comprising oxycodone 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.
Inventor(s):	Devarakonda; Krishna R. (St. Louis, MO), Giuliani; Michael J. (Creve Coeur, MO), Gupta; Vishal K. (Hillsborough, NJ), Heasley; Ralph A. (Webster Groves, MO), Shelby; Susan (Town and Country, MO)
Assignee:	MALLINCKRODT LLC (Hazelwood, MO)
Application Number:	14/627,879
Patent Claims:	1. A method of treating acute pain in a human subject comprising: administering to the subject in need thereof a solid oral dosage form comprising (a) at least one immediate release portion comprising acetaminophen in an amount selected from the group consisting of about 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 162.5 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, and 325 mg and oxycodone or a pharmaceutically acceptable salt thereof in an amount selected from the group consisting of about 1 mg, 1.25 mg, 1.3 mg, 1.325 mg, 1.35 mg, 1.375 mg, 1.4 mg, 1.425 mg, 1.45 mg, 1.475 mg, 1.5 mg, 1.525 mg, 1.55 mg, 1.575 mg, 1.6 mg, 1.625 mg, 1.65 mg, 1.675 mg, 1.7 mg, 1.725 mg, 1.75 mg, 1.775 mg, 1.8 mg, 1.825 mg, 1.85 mg, 1.875 mg, 1.9 mg, 1.925 mg, 1.95 mg, 1.975 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25 mg, 4.5 mg, and 4.75 mg; and (b) at least one extended release portion comprising acetaminophen in an amount selected from the group consisting of about 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 162.5 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, and 325 mg and oxycodone or a pharmaceutically acceptable salt thereof in an amount selected from the group consisting of about 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 5.625 mg, 6.0 mg, 6.5 mg, and 7.0 mg, wherein the total amount of acetaminophen in the solid oral dosage form is 325 mg and the total amount of oxycodone or a pharmaceutically acceptable salt in the solid oral dosage form is about 7.5 mg; and wherein upon administration of two solid oral dosage forms the subject attains therapeutic blood levels of both the oxycodone and the acetaminophen within about one hour after administration of the solid oral dosage forms and maintains analgesia for about 12 hours after administration of the solid oral dosage forms. 2. The method of claim 1, wherein the subject attains therapeutic blood levels of both the oxycodone and the acetaminophen within about 30 minutes after administration of the solid oral dosage forms. 3. The method of claim 1, wherein the subject attains therapeutic blood levels of both the oxycodone and the acetaminophen within about 15 minutes after administration of the solid oral dosage forms. 4. The method of claim 1, wherein upon administration to the subject, the solid oral dosage forms produce a plasma profile characterized by a biphasic absorption of the oxycodone. 5. The method of claim 4, wherein the biphasic absorption of the oxycodone provides for a quick onset of analgesia followed by maintenance of the oxycodone levels over an extended time period and prevents development of tolerance in the subject to the oxycodone at the active site. 6. The method of claim 1, wherein when orally administered to the subject, the solid oral dosage form produces a plasma profile characterized by a biphasic absorption of the acetaminophen. 7. The method of claim 6, wherein the biphasic absorption of the acetaminophen results in a first peak in the plasma concentration for the acetaminophen between about 0.5 hour and about 2 hours, which contributes to an early onset of analgesia, and a second peak in the plasma concentration for the acetaminophen between about 3 hours and about 7 hours which contributes to the duration or maintenance of analgesia. 8. The method on claim 7, wherein the slope of the plasma concentration-time profile for the acetaminophen between about 0 hour and about 2 hours is greater than the slope of a line drawn between about 2 hours and about 5 hours. 9. The method of claim 1, wherein the solid oral dosage form is administered to the subject in need thereof twice a day. 10. The method of claim 1, wherein the solid oral dosage form further comprises an extended release component. 11. The method of claim 10, wherein the extended release component is an extended release polymer. 12. The method of claim 11, wherein the extended release polymer is polyethylene oxide. 13. The method of claim 12, wherein the polyethylene oxide has a molecular weight from about 500,000 Daltons to about 10,000,000 Daltons. 14. A method of treating acute pain in a human subject over a 12-hour dosing cycle comprising: administering to the subject in need thereof a solid oral dosage form comprising (a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.5 mg of oxycodone or a pharmaceutically acceptable salt thereof, and (b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg of oxycodone or a pharmaceutically acceptable salt thereof, wherein the total amount of acetaminophen in the solid oral dosage form is 325 mg and the total amount of oxycodone or a pharmaceutically acceptable salt in the solid oral dosage form is about 7.5 mg; wherein upon placement of the solid oral dosage form 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.degree. C., the drug release profile substantially corresponds to the following: after 15 minutes, about 25% to about 35%, by weight, of the total amount of oxycodone or salt thereof in the solid oral dosage form is released and about 50% to about 55%, by weight, of the total amount of acetaminophen in the solid oral dosage form is released; after 1 hour, about 40% to about 50%, by weight, of the total amount of oxycodone or salt thereof in the solid oral dosage form is released and about 50% to about 65%, by weight, of the total amount of acetaminophen in the solid oral dosage form is released; and after 12 hours, from about 95% to about 100%, by weight, of the total amount of the oxycodone or salt is released and from about 90% to about 100%, by weight, of the total amount of the acetaminophen is released. 15. The method of claim 14, wherein the solid oral dosage form may be administered to the subject without regard to food. 16. The method according to claim 14, wherein more than about 80% of the acetaminophen in the immediate release portion is released within about 30 mins. 17. The method according to claim 14, wherein more than about 80% of the acetaminophen in the immediate release portion is released within about 15 mins. 18. The method according to claim 14, wherein more than about 80% of the oxycodone or pharmaceutically acceptable salt thereof in the immediate release portion is released within about 30 mins. 19. The method according to claim 14, wherein more than about 80% of the oxycodone or pharmaceutically acceptable salt thereof in the immediate release portion is released within about 15 mins. 20. The method according to claim 14, wherein more than about 90% of the acetaminophen in the immediate release portion is released within about 1 hour. 21. The method according to claim 14, wherein more than about 90% of the oxycodone or pharmaceutically acceptable salt thereof in the immediate release portion is released within about 1 hour. 22. A method of treating acute pain in a human subject over a 12-hour dosing cycle comprising: administering to the subject in need thereof a solid oral dosage form comprising (a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.5 mg of oxycodone or a pharmaceutically acceptable salt thereof, and (b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg of oxycodone or a pharmaceutically acceptable salt thereof, wherein the total amount of acetaminophen in the solid oral dosage form is 325 mg and the total amount of oxycodone or a pharmaceutically acceptable salt in the solid oral dosage form is about 7.5 mg; wherein upon administration of the solid oral dosage form the subject, the solid oral dosage form produces a mean AUC for oxycodone from about 12.0 nghr/mL/mg to about 16.0nghr/mL/mg and a mean AUC for acetaminophen from about 35.0 nghr/mL/mg to about 80.0 nghr/mL/mg. 23. The method of claim 22, wherein upon administration of the solid oral dosage form to the subject, the solid oral dosage form produces a C.sub.max for oxycodone from about 0.9 ng/mL/mg to about 1.6 ng/mL/mg and a C.sub.max for acetaminophen from about 4.0 ng/mL/mg to about 11.0 ng/mL/mg. 24. The method of claim 22, wherein upon administration of the solid oral dosage form to the subject, the solid oral dosage form produces a T.sub.max for oxycodone from about 2 hours to about 7 hours, and a T.sub.max for acetaminophen from about 0.5 hour to about 6 hours. 25. The method of claim 22, wherein upon administration of the solid oral dosage form to the subject, the solid oral dosage form produces a C.sub.max for acetaminophen within about 0.75 hours to about 1.5 hours. 26. The method of claim 22, wherein upon administration of the solid oral dosage form to the subject, the solid oral dosage form produces a C.sub.max for acetaminophen within about one hour. 27. The method of claim 22, wherein upon administration of the solid oral dosage form to the subject, the solid oral dosage form produces a C.sub.max for oxycodone within about 1.5 hours to about 3.5 hours. 28. The method of claim 22, wherein upon administration of the solid oral dosage form to the subject, the solid oral dosage form produces a C.sub.max for oxycodone within about 3 hours to about 4 hours.