Combination composition comprising oxycodone and acetaminophen for rapid onset and extended duration of analgesia

• US 8,658,631 B1
• Filed: 05/16/2012
• Issued: 02/25/2014
• 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, Guiliani, Michael J, Gupta, Vishal K, Heasley, Ralph A, Shelby, Susan
• Primary Examiner(s): Lundgren, Jeffrey S.
• Assistant Examiner(s): OLABOWALE, ZENAB O
• Application Number:
  US13/473,563
• Time in Patent Office: 650 Days
• Field of Search: 514/183
• US Class Current: 514/183
• 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 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.

Claims

1. A pharmaceutical composition 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 4.0 mg 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 oxycodone or salt thereof, 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 10 mg, 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 about 37°

C., about 25% to about 35% of the total amount of oxycodone or salt thereof in the composition is released at about 15 minutes in the test and about 50% to about 55% of the total amount of acetaminophen in the composition is released at about 15 minutes in the test.

2. The pharmaceutical composition of claim 1,

wherein upon oral administration of a single dose of the composition to a subject, the composition provides a C_max for oxycodone from about 0.9 ng/mL/mg to about 1.6 ng/mL/mg, a C_max for acetaminophen from about 4.0 ng/mL/mg to about 11.0 ng/mL/mg, a T_max for oxycodone from about 2 hours to about 7 hours, and a T_max for acetaminophen from about 0.5 hour to about 6 hours.

3. The pharmaceutical composition of claim 1, wherein from about 50% to about 65%, by weight, of the oxycodone or salt is released from the composition at about 2 hours in the test, from about 70% to about 85%, by weight, of the oxycodone or salt is released from the composition at about 4 hours in the test, from about 90% to about 100%, by weight, of the oxycodone or salt is released from the composition at about 8 hours in the test, from about 60% to about 75%, by weight, of the acetaminophen is released from the composition at about 2 hours in the test, and from about 75% to about 85%, by weight, of the acetaminophen is released from the composition at about 4 hours in the test.

4. The pharmaceutical composition of claim 1, wherein upon oral administration of multiple doses to a subject in need of analgesia, the composition produces a blood plasma profile characterized by a mean AUC for oxycodone from about 12.0 ng·

hr/mL/mg to about 16.0 ng·

hr/mL/mg, a steady state AUC for oxycodone from about 13.0 ng·

hr/mL/mg to about 15.0 ng·

hr/mL/mg, a mean AUC for acetaminophen from about 35.0 ng·

hr/mL/mg to about 80.0 ng·

hr/mL/mg, and a steady state AUC for acetaminophen from about 37.0 ng·

hr/mL/mg to about 42.0 ng·

hr/mL/mg.

5. The pharmaceutical composition of claim 1, wherein upon oral administration of multiple doses to a subject in need of analgesia, the composition produces a blood plasma profile characterized by a median T_max for oxycodone from about 3.0 hours to about 6.0 hours, a steady state T_max for oxycodone from about 2.0 hours to about 3.0 hours, a median T_max for acetaminophen from about 1.0 hour to about 5.0 hours, and a steady state T_max for acetaminophen from about 0.5 hour to about 1.0 hours.

6. The pharmaceutical composition of claim 1, 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 about 37°

C., about 34% to about 40% of the oxycodone or salt thereof is released at about 30 minutes in the test and about 51% to about 58% of the acetaminophen is released at about 30 minutes in the test.

7. The pharmaceutical composition of claim 1, wherein the extended release component comprises polyethylene oxide.

8. The pharmaceutical composition of claim 7, wherein the polyethylene oxide has a molecular weight from about 500,000 Daltons to about 10,000,000 Daltons.

9. The pharmaceutical composition of claim 1, wherein the at least one immediate release portion comprises from about 20% to about 30% of the total amount of oxycodone 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 oxycodone and acetaminophen.

10. The pharmaceutical composition of claim 1, 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;

and the extended release portion comprises, by weight of the extended release portion, from about 30% to about 50% of the extended release component, from about 20% to about 40% of acetaminophen, and from about 0.5% to about 2% of oxycodone.

11. The pharmaceutical composition of claim 1, wherein the extended release component comprises a polymer selected from the group consisting of linear, branched, dendrimeric, or star polymers, hydrophilic polymers, and mixtures thereof.

12. The pharmaceutical composition of claim 1, wherein the extended release component comprises a polymer selected from the group consisting of a polyalkylene oxide, poly(ethylene oxide), polyethylene glycol and poly(ethylene oxide) poly(propylene oxide), methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, aminoethyl acrylate, maleic anhydride copolymer, polymaleic acid, poly(acrylamide), poly(methacrylamide), poly(dimethylacrylamide), poly(N-isopropyl-acrylamide), poly(olefinic alcohol), poly(vinyl alcohol), poly(N-vinyl lactam), poly(vinyl pyrrolidone), poly(N-vinyl caprolactam), polyol, glycerol, polyglycerol, propylene glycol, trimethylene glycol, mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, mono- and di-polyoxyethylated trimethylene glycol, polyoxyethylated sorbitol, polyoxyethylated glucose, polyoxazolines, poly(methyloxazoline), poly(ethyloxazoline), polyvinylamine, polyvinylacetate, ethylene-vinyl acetate copolymer, polyvinyl acetate phthalate, polyimines, polyethyleneimine, starch, starch-based polymer, polyurethane hydrogel, chitosan, polysaccharide gums, xanthan gum, zein, shellac, ammoniated shellac, shellac-acetyl alcohol, shellac n-butyl stearate, and mixtures thereof.

27. The pharmaceutical composition of claim 1, wherein the composition is administered to a subject as bilayer tablet.

28. The pharmaceutical composition of claim 27, wherein a single dose comprises two bilayer tablets.

13. A pharmaceutical composition 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 4.0 mg 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 oxycodone or salt thereof, 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 10 mg;

wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 150 rpm in 900 mL of 0.1N HCl using a USP type II apparatus at a constant temperature of about 37°

C., the drug release profile substantially corresponds to the following;

after 15 minutes, no more than about 35%, by weight, of the total amount of the oxycodone or salt is released and no more than about 55%, by weight, of the total amount of the acetaminophen is released;

after 1 hour, no more than about 50%, by weight, of the total amount of the oxycodone or salt is released and no more than about 63%, by weight, of the total amount of the acetaminophen 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.

14. The pharmaceutical composition of claim 13, wherein the composition comprises about 325 mg of acetaminophen and about 7.5 mg of oxycodone.

15. The pharmaceutical composition of claim 13, wherein when orally administered to a subject, the composition produces a blood plasma concentration profile characterized by a biphasic increase in blood plasma concentrations of oxycodone and acetaminophen.

16. The pharmaceutical composition of claim 15, wherein the biphasic increase in blood plasma concentrations of oxycodone is characterized by a plasma concentration-time profile for oxycodone in which the slope of a line drawn between 0 hour and about 2 hours is greater than the slope of a line drawn between about 2 hours and about 5 hours.

17. A pharmaceutical composition as 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 4.0 mg 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 oxycodone or salt thereof, and an extended release component;

wherein the total amount of acetaminophen in the composition is about 325 mg, and the total amount of oxycodone or salt in the composition is about 7.5 mg;

wherein upon oral administration of two solid oral dosage forms of the composition in multiple doses in an amount of about 15 mg oxycodone or salt and about 650 mg acetaminophen, the composition provides an AUC_0-1.7h for acetaminophen of about 5.0 ng·

h/mL/mg to about 13.0 ng·

h/mL/mg;

an AUC_1.7-48h for acetaminophen of about 25.0 ng·

h/mL/mg to about 75.0 ng·

h/mL/mg, an AUC_0-2.8h, for oxycodone or salt of about 1.0 ng h/mL/mg to about 3.0 ng·

h/mL/mg; and

AUC_2.8-48h of about 7.5 ng·

h/mL/mg to about 15.0 ng·

h/mL/mg.

18. The pharmaceutical composition of claim 17 wherein the AUC_0-1hr for acetaminophen is from about 1.25 ng·

hr/mL/mg to about 3.25 ng·

hr/mL/mg.

19. The pharmaceutical composition of claim 17 wherein the AUC_0-2hr for acetaminophen is from about 4.25 ng·

hr/mL/mg to about 8.75 ng·

hr/mL/mg.

21. The pharmaceutical composition of claim 17 wherein the AUC_0-2hr for oxycodone is from about 0.65 ng·

hr/mL/mg to about 1.35 ng·

hr/mL/mg.

22. The pharmaceutical composition of claim 17 wherein the AUC_0-4hr for oxycodone is from about 2.0 ng·

hr/mL/mg to about 4.0 ng·

hr/mL/mg.

29. The solid oral dosage form of claim 17, wherein the solid oral dosage form is a tablet of capsule.

20. The pharmaceutical composition of claim wherein the AUC_0-4hr for acetaminophen is from about 10.0 ng·

hr/mL/mg to about 20.0 ng·

hr/mL/mg.

23. A pharmaceutical composition as a solid oral dosage form for oral administration useful in the treatment of pain and for reducing the risk of acetaminophen-induced hepatic damage, 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 4.0 mg 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 oxycodone or salt thereof, 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 10 mg; and

wherein upon oral administration of two solid oral dosage forms of the composition in an amount of about 15 mg oxycodone or salt and about 650 mg acetaminophen the composition maintains a therapeutic blood plasma concentration of oxycodone of at least about 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.

24. The pharmaceutical composition of claim 23, wherein upon oral administration depleted stores of hepatic glutathione are able to be substantially replenished during the later part of a dosing internal when plasma concentrations of acetaminophen are reduced.

25. The pharmaceutical composition of claim 23, wherein the AUC_Tmax-t for acetaminophen is from about 20.0 ng·

hr/mL/mg to about 40.0 ng·

hr/mL/mg.

26. The pharmaceutical composition of claim 23, wherein the AUC_(1.7-48) for acetaminophen is from about 25.0 ng·

hr/mL/mg to about 75.0 ng·

hr/mL/mg.

30. The solid oral dosage form of claim 23, wherein the solid oral dosage form is used in the treatment of acute pain.