GASTRIC RETENTIVE EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS

• US 20140105977A1
• Filed: 12/18/2013
• Published: 04/17/2014
• Est. Priority Date: 05/17/2011
• Status: Active Grant

• Current Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Original Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Inventors: DEVARAKONDA, KRISHNA R., GIULIANI, MICHAEL J., GUPTA, VISHAL K., HEASLEY, RALPH A., SHELBY, SUSAN
• Granted Patent: US 8,790,694 B2
• Time in Patent Office: Days
• US Class Current: 424/468
• 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 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0065 Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
• 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 9/209 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 an opioid and an additional active pharmaceutical ingredient, wherein the composition exhibits gastric retentive properties which are achieved by a combination of a physical property of the composition and release of the opioid, wherein upon administration to a subject, the composition has at least one pharmacokinetic parameter that differs by less than about 30% when the subject is in a fasted state as compared to a fed state.

Claims

1. A pharmaceutical composition, comprising:

an immediate release portion comprising, by total weight of the immediate release portion, about 0.5% to about 2.5% of hydrocodone or a pharmaceutically acceptable salt of hydrocodone, and about 65% to about 85% of acetaminophen; and

an extended release portion comprising, by total weight of the extended release portion, about 0.3% to about 1.0% of hydrocodone or a pharmaceutically acceptable salt of hydrocodone and about 15% to about 25% of acetaminophen;

wherein the total amount of acetaminophen in the composition is about 200 mg to about 650 mg, and the total amount of hydrocodone or a pharmaceutically acceptable salt of hydrocodone in the composition is about 5 mg to about 15 mg;

wherein when the composition is orally administered to a subject in need thereof the composition delivers the hydrocodone or the pharmaceutically acceptable salt thereof and the acetaminophen to the subject'"'"'s upper gastrointestinal tract for at least about 4 hours to about 12 hours; and

wherein either the hydrocodone or the acetaminophen produces a plasma profile characterized by at least one pharmacokinetic parameter selected from the group consisting of C_max, C_{1 hr}, C_{2 h}, AUC, partial AUC, T_max, and T_lag that differs by less than about 30% when the subject is in a fasted state as compared to a fed state.

2. The pharmaceutical composition of claim 1, wherein the pharmacokinetic parameter selected from the group consisting of C_max, C_{1 hr}, C_{2 h}, AUC, partial AUC, T_max, and T_lag differs by less than about 20%.

3. The pharmaceutical composition of claim 1, wherein the pharmacokinetic parameter is selected from the group consisting of AUC and C_max.

4. The pharmaceutical composition of claim 1, wherein both the hydrocodone and the acetaminophen produce a plasma profile characterized by at least one pharmacokinetic parameter selected from the group consisting of C_max, C_{1 hr}, C_{2 h}, AUC, partial AUC, T_max, and T_lag that differs by less than about 30% when the subject is in a fasted state as compared to a fed state.

5. The pharmaceutical composition of claim 1, wherein the composition is a bilayer tablet.

6. The pharmaceutical composition of claim 1, wherein the extended release portion comprises at least one extended release polymer.

7. The pharmaceutical composition of claim 6, wherein the at least one extended release polymer is a 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 6, wherein the at least one extended release polymer absorbs water and swells to a size sufficient for gastric retention.

10. The pharmaceutical composition of claim 1, wherein the total amount of the acetaminophen in the composition is about 325 mg;

and the total amount of the hydrocodone or the pharmaceutically acceptable salt thereof in the composition is about 7.5 mg.

11. The pharmaceutical composition of claim 1, wherein the composition delivers the hydrocodone or the pharmaceutically acceptable salt thereof and the acetaminophen to the subject'"'"'s upper gastrointestinal tract for at least about 6 hours.

12. The pharmaceutical composition of claim 1, wherein the composition comprises (a) two immediate release portions in which one of the immediate release portions contains the hydrocodone or the pharmaceutically acceptable salt thereof and the other immediate release portion contains the acetaminophen, and (b) two extended release portions in which one of the extended release portions contains the hydrocodone or the pharmaceutically acceptable salt thereof and the other extended release portion contains the acetaminophen.

13. The pharmaceutical composition of claim 1, wherein the composition is gastric retentive.

14. 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 at least one extended release portion comprises from about 70% to about 80% (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 sum of the amounts of the acetaminophen in the immediate release and the extended release portions is about 325 mg;

wherein the sum of the amounts of the hydrocodone or pharmaceutically acceptable salt thereof in the immediate release and extended release portions is about 7.5 mg; and

wherein the bioavailability of the acetaminophen and the hydrocodone or the pharmaceutically acceptable salt thereof is not affected by the absence of food in a subject'"'"'s gastrointestinal tract.

15. The pharmaceutical composition of claim 14, wherein when the pharmaceutical composition is administered to a subject under fasted conditions, the mean AUC for hydrocodone of the subject is about 9.0 ng·

hr/mL/mg to about 24.0 ng·

hr/mL/mg and the mean AUC for acetaminophen of the subject is about 35.0 ng·

hr/mL/mg to about 80.0 ng·

hr/mL/mg.

16. The pharmaceutical composition of claim 14, wherein when the pharmaceutical composition is administered to a subject under fasted conditions, the Cmax for hydrocodone of the subject is about 0.9 ng/mL/mg to about 2.0 ng/mL/mg and the Cmax for acetaminophen of the subject is about 6 ng·

hr/mL/mg to about 9 ng·

hr/mL/mg.

17. The pharmaceutical composition of claim 14, wherein the composition is a bilayer tablet.

18. A pharmaceutical composition, comprising:

an immediate release portion comprising about 20% to about 30% (w/w) of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof in the composition, and about 40% to about 60% (w/w) of the total amount of the acetaminophen in the composition; and

an extended release portion comprising about 70% to about 80% (w/w) of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof in the composition, 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 200 mg to about 650 mg, and the total amount of hydrocodone or pharmaceutically acceptable salt thereof in the composition is about 5 mg to about 15 mg;

wherein when the composition is orally administered to a subject in need thereof the composition delivers the hydrocodone or the pharmaceutically acceptable salt thereof and the acetaminophen to the subject'"'"'s upper gastrointestinal tract for at least about 4 hours; and

wherein either the hydrocodone or the acetaminophen produces a plasma profile characterized by at least one pharmacokinetic parameter selected from the group consisting of C_max, C_{1 hr}, C_{2 h}, AUC, partial AUC, T_max, and T_lag that differs by less than about 30% when the subject is in a fasted state as compared to a fed state.

19. The pharmaceutical composition of claim 18, wherein the composition is a solid oral dosage form.

20. The pharmaceutical composition of claim 18, wherein the composition comprises about 325 mg of acetaminophen and about 7.5 mg of hydrocodone or pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of claim 18, wherein the composition further comprises at least one extended release polymer.

22. The pharmaceutical composition of claim 21, wherein the extended release polymer comprises a polymer selected from the group consisting of linear, branched, dendrimeric, or star polymers, hydrophilic polymers, and mixtures thereof.

23. The pharmaceutical composition of claim 18, wherein when the pharmaceutical composition is administered to a subject under fasted conditions, the mean AUC for hydrocodone of the subject is about 9.0 ng·

hr/mL/mg to about 24.0 ng·

hr/mL/mg and the mean AUC for acetaminophen of the subject is about 35.0 ng·

hr/mL/mg to about 80.0 ng·

hr/mL/mg.

24. The pharmaceutical composition of claim 18, wherein when the pharmaceutical composition is administered to a subject under fasted conditions, the Cmax for hydrocodone of the subject is about 0.9 ng/mL/mg to about 2.0 ng/mL/mg and the Cmax for acetaminophen of the subject is about 6 ng·

hr/mL/mg to about 9 ng·

hr/mL/mg.

25. The pharmaceutical composition of claim 18, wherein when the pharmaceutical composition is administered to a subject under fed conditions, the mean AUC for hydrocodone of the subject is about 9.0 ng·

hr/mL/mg to about 24.0 ng·

hr/mL/mg and the mean AUC for acetaminophen of the subject is about 35.0 ng·

hr/mL/mg to about 80.0 ng·

hr/mL/mg.

26. The pharmaceutical composition of claim 18, wherein when the pharmaceutical composition is administered to a subject under fed conditions, the Cmax for hydrocodone of the subject is about 0.9 ng/mL/mg to about 2.0 ng/mL/mg and the Cmax for acetaminophen of the subject is about 6 ng·

hr/mL/mg to about 9 ng·

hr/mL/mg.

27. A solid oral dosage form, comprising:

an immediate release portion comprising about 20% to about 30% (w/w) of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof in the dosage form, and about 40% to about 60% (w/w) of the total amount of the acetaminophen in the dosage form; and

an extended release portion comprising about 70% to about 80% (w/w) of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof in the dosage form, and about 40% to about 60% (w/w) of the total amount of the acetaminophen in the dosage form;

wherein the total amount of hydrocodone or pharmaceutically acceptable salt thereof in the dosage form is about 7.5 mg and the total amount of acetaminophen in the dosage form is about 325 mg;

wherein the dosage form has gastric retentive properties; and

wherein the bioavailability of either the acetaminophen or the hydrocodone or the pharmaceutically acceptable salt thereof is not affected by the absence of food in a subject'"'"'s gastrointestinal tract.

28. The solid oral dosage form of claim 27, wherein when the pharmaceutical composition is administered to a subject under fasted conditions, the mean AUC for hydrocodone of the subject is about 10.0 ng·

hr/mL/mg to about 22.0 ng·

hr/mL/mg and the mean AUC for acetaminophen of the subject is about 35.0 ng·

hr/mL/mg to about 60.0 ng·

hr/mL/mg.

29. The solid oral dosage form of claim 27, wherein when the pharmaceutical composition is administered to a subject under fasted conditions, the Cmax for hydrocodone of the subject is about 1.1 ng/mL/mg to about 2.0 ng/mL/mg and the Cmax for acetaminophen of the subject is about 6.5 ng·

hr/mL/mg to about 8.5 ng·

hr/mL/mg.

30. The solid oral dosage form of claim 27, wherein when the pharmaceutical composition is administered to a subject under fasted conditions, the Tmax for hydrocodone of the subject is about 2 hours to about 4 hours and the Tmax for acetaminophen of the subject is about 0.5 hours to about 4 hours.