Controlled release hydrocodone formulations

• US 7,514,100 B2
• Filed: 09/11/2003
• Issued: 04/07/2009
• Est. Priority Date: 10/30/2000
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Oshlack, Benjamin, Masselink, John K., Tonelli, Alfred P., Huang, Hua-Pin
• Primary Examiner(s): Sheikh; Humera N
• Application Number:
  US10/660,349
• Publication Number:
  US 20040047907A1
• Time in Patent Office: 2,035 Days
• Field of Search: 424/464, 424/468, 424/472
• US Class Current: 424/473
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/141 Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers (co) spray-dried products A61K9/16, (co) lyophilised products A61K9/19; the carrier being chemically bound to the active ingredient A61K47/50
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• 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 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

A solid oral controlled-release dosage form of hydrocodone is disclosed, the dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and controlled release material.

Claims

1. A solid oral controlled-release dosage form suitable for 24 hour dosing of an active agent in a human patient comprising a pharmaceutically acceptable matrix comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and controlled release material;

said dosage form after administration to a human patient, providing a C₂₄/C_max ratio of 0.55 to about 0.85;

a therapeutic effect for at least about 24 hours and a dissolution release rate in-vitro of the hydrocodone or salt thereof, when measured by the USP Basket Method at 100 rpm in 700 ml Simulated Gastric Fluid (SGF) at 37°

C. for 1 hour and thereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at 37°

C., wherein at least 20% by weight hydrocodone or salt thereof is released at 4 hours, from about 20% to about 65% by weight hydrocodone or salt thereof is released at 8 hours, from about 45% to about 85% by weight hydrocodone or salt thereof is released at 12 hours, and at least 80% by weight hydrocodone or salt thereof is released at 24 hours.

2. The dosage form of claim 1, which provides a C₂₄/C_max ratio of 0.55 to 0.75.

3. The dosage form of claim 1, wherein said matrix is a plurality of multiparticulate matrices.

4. The dosage form of claim 3, wherein said multiparticulate matrices are compressed into a tablet.

5. The dosage form of claim 3, wherein said multiparticulate matrices are disposed in a pharmaceutically acceptable capsule.

6. The dosage form of claim 1 which provides a C₂₄/C_max ratio of 0.60 to 0.70.

7. The dosage form of claim 1 which provides a dissolution release rate in-vitro of the hydrocodone when measured by the USP Basket method at 100 rpm in 700 ml aqueous buffer at a pH of 1.2 at 37°

C. is at least 10% to about 45% by weight hydrocodone or salt thereof released at 1 hour.

8. The dosage form of claim 1, which provides a time to maximum plasma concentration (T_max) of hydrocodone at about 4 to about 14 hours after oral administration of the dosage form.

9. The dosage form of claim 1, which provides a time to maximum plasma concentration (T_max) of hydrocodone at about 6 to about 12 hours after oral administration of the dosage form.

10. The dosage form of claim 1, which provides a C_max of hydrocodone which is less than 60% of the C_max of an equivalent dose of an immediate release hydrocodone reference formulation.

11. The dosage form of claim 1, wherein said administration is first administration.

12. The dosage form of claim 1, wherein said administration is steady state administration.

13. The dosage form of claim 1, wherein said ratio is obtained from a population of patients.

33. The dosage form of claim 1, further comprising a non-opioid drug.

34. The dosage form of claim 33, wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

14. A solid oral controlled-release dosage form suitable for 24 hour dosing of an active agent in a human patient comprising a plurality of pharmaceutically acceptable beads coated with an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and overcoated with a pH-independent hydrophobic material comprising an acrylic polymer, said dosage form providing an in-vitro release rate, of hydrocodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C., of from 0% to about 35% at 1 hour, from about 10% to about 70% at 4 hours, from about 20% to about 75% at 8 hours, from about 30% to about 80% at 12 hours, from about 40% to about 90% at 18 hours, and greater than about 60% at 24 hours;

the in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of opioid released at one pH and an amount released at any other pH, when measured in-vitro using the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100 rpm in 900 ml aqueous buffer, is no greater than 10%;

said dosage form providing a C₂₄/C_max ratio of 0.55 to about 0.85; and

a therapeutic effect for at least 24 hours, after oral administration to a human patient.

15. The dosage form of claim 14, which provides a C₂₄/C_max ratio of 0.55 to 0.75.

16. The dosage form of claim 14, which provides a time to maximum plasma concentration (T_max) of hydrocodone at about 4 to about 14 hours after oral administration of the dosage form.

17. The dosage form of claim 14, which provides a time to maximum plasma concentration (T_max) of hydrocodone at about 6 to about 12 hours after oral administration of the dosage form.

18. The dosage form of claim 14, which provides a C_max of hydrocodone which is less than 60% of the C_max of an equivalent dose of an immediate release hydrocodone reference formulation.

19. The dosage form of claim 14, wherein said administration is first administration.

20. The dosage form of claim 14, wherein said administration is steady state administration.

21. The dosage form of claim 14, wherein said ratio is obtained from a population of patients.

22. A method of providing effective analgesia in a human patient for at least about 24 hours comprising orally administering a dosage form of claim 14 to a human patient.

35. The dosage form of claim 14, further comprising a non-opioid drug.

36. The dosage form of claim 35, wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

23. A sustained release oral dosage form comprising:

(a) a bilayer core comprising;

(i) a drug layer comprising an analgesically effective amount of an active agent comprising hydrocodone or a pharmaceutically acceptable salt thereof; and

(ii) a displacement layer comprising an osmopolymer; and

(b) a semipermeable wall comprising a hydrophobic material selected from the group consisting of a cellulosic polymer, an acrylic polymer and a combination thereof surrounding the bilayer core and having a passageway disposed therein for the release of said hydrocodone or pharmaceutically acceptable salt thereof;

said dosage form providing a C₂₄/C_max ratio of 0.55 to about 0.85;

a therapeutic effect for at least about 24 hours after oral administration to a human patient and a dissolution release rate in-vitro of the hydrocodone or salt thereof, when measured by the USP Basket Method at 100 rpm in 700 ml Simulated Gastric Fluid (SGF) at 37°

C. for 1 hour and thereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at 37°

C., wherein at least 20% by weight hydrocodone or salt thereof is released at 4 hours, from about 20% to about 65% by weight hydrocodone or salt thereof is released at 8 hours, from about 45% to about 85% by weight hydrocodone or salt thereof is released at 12 hours, and at least 80% by weight hydrocodone or salt thereof is released at 24 hours.

24. The dosage form of claim 23, which provides a C₂₄/C_max ratio of 0.55 to 0.75.

25. The dosage form of claim 23, which provides a time to maximum plasma concentration (T_max) of hydrocodone at about 4 to about 14 hours after oral administration of the dosage form.

26. The dosage form of claim 23, which provides a time to maximum plasma concentration (T_max) of hydrocodone at about 6 to about 12 hours after oral administration of the dosage form.

27. The dosage form of claim 23, which provides a C_max of hydrocodone which is less than 60% of the C_max of an equivalent dose of an immediate release hydrocodone reference formulation.

28. The dosage form of claim 23, wherein said administration is first administration.

29. The dosage form of claim 23, wherein said administration is steady state administration.

30. The dosage form of claim 23, wherein said ratio is obtained from a population of patients.

37. The dosage form of claim 23 further comprising a non-opioid drug.

38. The dosage form of claim 37, wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

31. A sustained release oral dosage form comprising:

(a) a bilayer core comprising;

(i) a drug layer comprising an active agent comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof; and

(ii) a displacement layer comprising an osmopolymer; and

(b) a semipermeable wall comprising a hydrophobic material selected from the group consisting of a cellulosic polymer, an acrylic polymer and a combination thereof surrounding the bilayer core and having a passageway disposed therein for the release of said hydrocodone or pharmaceutically acceptable salt thereof;

said dosage form providing an in-vitro release rate, of hydrocodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. of from 0% to about 35% at 1 hour, from about 10% to about 70% at 4 hours, from about 20% to about 75% at 8 hours, from about 30% to about 80% at 12 hours, from about 40% to about 90% at 18 hours, and greater than about 60% at 24 hours;

the in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of opioid released at one pH and an amount released at any other pH, when measured in-vitro using the USP Paddle Method of U.S. Pharmacopoeia XXII (1990) at 100 rpm in 900 ml aqueous buffer, is no greater than 10%.

32. A method of providing effective analgesia in a human patient for at least about 24 hours comprising orally administering a dosage form of claim 31 to a human patient.

39. The dosage form of claim 31, further comprising a non-opioid drug.

40. The dosage form of claim 39, wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

41. The method of claim 32, wherein the dosage form , also contains a non-opioid drug.

42. The method of claim 41, wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.