Pharmaceutical compositions for extended release of oxycodone and acetaminophen resulting in a quick onset and prolonged period of analgesia

• US 9,050,335 B1
• Filed: 05/16/2012
• Issued: 06/09/2015
• Est. Priority Date: 05/17/2011
• Status: Expired due to Fees

• Current Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Original Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Inventors: Devarakonda, Krishna, Giuliani, Michael J., Gupta, Vishal K., Heasley, Ralph A., Shelby, Susan
• Primary Examiner(s): Soroush, Ali
• Application Number:
  US13/473,586
• Time in Patent Office: 1,119 Days
• Field of Search: 424/468, 514/282, 514/731
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer

Abstract

The present disclosure provides extended release pharmaceutical compositions comprising oxycodone and acetaminophen that produce a quick initial onset of analgesia, yet, maintain analgesia for about 12 hours after administration of the composition to a subject in need thereof. The pharmaceutical compositions disclosed herein also reduce the levels of acetaminophen in a subject'"'"'s blood near the end of the dosing interval because the acetaminophen released by the pharmaceutical composition is being eliminated by a subjects body faster than it is being absorbed.

Claims

1. A pharmaceutical composition for extended release of oxycodone and acetaminophen, comprising:

at least one extended release portion comprising oxycodone or a pharmaceutically acceptable salt of oxycodone, 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 oxycodone or salt in the composition is about 7.5 mg to about 15 mg;

wherein upon oral administration of the composition to a subject in a fasted state, the composition provides an AUC_0-1.7h for acetaminophen of about 5 ng·

h/ml/mg to about 13 ng·

h/ml/mg;

an AUC_1.7-48h for acetaminophen of about 25 ng·

h/ml/mg to about 75 ng·

h/ml/mg;

an AUC_0-2.8h for oxycodone or salt of about 1 ng·

h/ml/mg to about 3 ng·

h/ml/mg; and

AUC_2.8-48h for oxycodone or salt of about 7.5 ng·

h/ml/mg to about 15 ng·

h/ml/mg.

2. The pharmaceutical composition of claim 1, wherein the AUC_0-1.7h for acetaminophen is about 8.5 ng·

h/ml/mg to about 10 ng·

h/ml/mg.

3. The pharmaceutical composition of claim 1, wherein the AUC_1.7-48h for acetaminophen is about 35 ng·

h/ml/mg to about 50 ng·

h/ml/mg.

4. The pharmaceutical composition of claim 1, wherein the AUC_0-2.8h for oxycodone or salt is about 2.5 ng·

h/ml/mg to about 3.5 ng·

h/ml/mg.

5. The pharmaceutical composition of claim 1, wherein the AUC_2.8-48h for oxycodone or salt is about 9.5 ng·

h/ml/mg to about 11.5 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 oxycodone or salt.

7. The pharmaceutical composition of claim 1, wherein the composition comprises about 325 mg of acetaminophen and about 7.5 mg of oxycodone 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 oxycodone or a pharmaceutically acceptable salt of oxycodone, 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 oxycodone 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 oxycodone or salt and the acetaminophen.

14. The pharmaceutical composition of claim 12, wherein the composition comprises (a) one immediate release portion comprising the oxycodone or salt and the acetaminophen, and (b) one extended release portion comprising the extended release polymer, the oxycodone 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 oxycodone 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 oxycodone or salt.

16. A pharmaceutical composition for extended release of oxycodone and acetaminophen, comprising:

at least one extended release portion comprising oxycodone or a pharmaceutically acceptable salt of oxycodone, 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 oxycodone or salt in the composition is about 7.5 mg to about 15 mg;

wherein upon oral administration of the composition to a subject in a fed state, the composition provides an AUC_0-3.2h for acetaminophen of about 7 ng·

h/mL/mg to about 21 ng·

h/mL/mg;

an AUC_3.2-48h for acetaminophen of about 15 ng·

h/mL/mg to about 75 ng·

h/mL/mg;

an AUC_0-4.3h for oxycodone or salt of about 1.5 ng·

h/mL/mg to about 5.5 ng·

h/mL/mg; and

AUC_4.3-48h for oxycodone or salt of about 5.0 ng·

h/mL/mg to about 15 ng·

h/mL/mg.

17. The pharmaceutical composition of claim 16, wherein the AUC_0-3.2h for acetaminophen is about 12 ng·

h/mL/mg to about 15 ng·

h/mL/mg.

18. The pharmaceutical composition of claim 16, wherein the AUC_3.2-48h for acetaminophen is about 30 ng·

h/mL/mg to about 40 ng·

h/mL/mg.

19. The pharmaceutical composition of claim 16, wherein the AUC_0-4.3h for oxycodone or salt is about 3.0 ng·

h/ml/mg to about 4.0 ng·

h/ml/mg.

20. The pharmaceutical composition of claim 16, wherein the AUC_4.3-48h for oxycodone or salt is about 9.5 ng·

h/ml/mg to about 11.5 ng·

h/ml/mg.

21. The pharmaceutical composition of claim 16, wherein the composition comprises about 650 mg of acetaminophen and about 15 mg of oxycodone or salt.

22. The pharmaceutical composition of claim 16, wherein the composition comprises about 325 mg of acetaminophen and about 7.5 mg of oxycodone or salt.

23. The pharmaceutical composition of claim 22, wherein the composition is in the form of a tablet and a single dose comprises two tablets.

24. The pharmaceutical composition of claim 16, wherein the extended release component comprises at least one extended release polymer.

25. The pharmaceutical composition of claim 24, wherein the at least one extended release polymer is a polyethylene oxide.

26. The pharmaceutical composition of claim 25, wherein the molecular weight of the polyethylene oxide is from about 500,000 Daltons to about 10,000,000 Daltons.

27. The pharmaceutical composition of claim 16, wherein the composition further comprises at least one immediate release portion comprising oxycodone or a pharmaceutically acceptable salt of oxycodone, acetaminophen, or a combination thereof.

28. The pharmaceutical composition of claim 27, wherein the at least one immediate release portion comprises from about 20% to about 30% of the total amount of oxycodone 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 oxycodone or salt and the acetaminophen.

29. The pharmaceutical composition of claim 27, wherein the composition comprises (a) one immediate release portion comprising the oxycodone or salt and the acetaminophen, and (b) one extended release portion comprising the extended release polymer, the oxycodone or salt and the acetaminophen.

30. The pharmaceutical composition of claim 29, 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 oxycodone 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 oxycodone or salt.

31. An extended release pharmaceutical composition, comprising:

at least one extended release portion comprising oxycodone or a pharmaceutically acceptable salt of oxycodone, 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 oxycodone 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 oxycodone 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 15 minutes, about 25% to about 35%, by weight, of the total amount of oxycodone or salt thereof in the composition is released and about 50% to about 55%, by weight, of the total amount of acetaminophen in the composition is released;

after 1 hour, about 40% to about 50%, by weight, of the total amount of oxycodone or salt thereof in the composition is released and about 50% to about 65%, by weight, of the total amount of acetaminophen in the composition is released;

after 2 hours, no more than about 65%, by weight, of the total amount of the oxycodone or salt is released and no more than about 75%, 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 oxycodone or salt is released and from about 70% to about 90%, by weight, of the total amount of the acetaminophen is released;

after 8 hours, from about 85% to about 100%, by weight, of the total amount of the oxycodone or salt is released and from about 85% to about 100%, by weight, of the total amount of the acetaminophen 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.