Controlled release hydrocodone formulations

• US 8,975,273 B2
• Filed: 09/11/2014
• Issued: 03/10/2015
• Est. Priority Date: 10/29/1999
• Status: Expired due to Fees

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Oshlack, Benjamin, Huang, Hua-Pin, Masselink, John, Tonelli, Alfred P.
• Primary Examiner(s): BASQUILL, SEAN M
• Application Number:
  US14/483,395
• Publication Number:
  US 20140377348A1
• Time in Patent Office: 180 Days
• Field of Search: 424/456, 424/457, 424/468, 424/494, 424/496, 424/497, 514/282
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0087 Galenical forms not covered by A61K9/02 - A61K9/7023
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• 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 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/282 Organic compounds, e.g. fats
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids

Abstract

A solid oral controlled-release oral dosage form of hydrocodone is disclosed. The dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a sufficient amount of a controlled release material to render the dosage form suitable for twice-a-day administration to a human patient, the dosage form providing a C₁₂/C_max ratio of 0.55 to 0.85, said dosage form providing a therapeutic effect for at least about 12 hours.

Claims

1. A solid oral controlled-release dosage form, the dosage form comprising a compressed tablet comprising

a plurality of multiparticulates collectively consisting essentially of from about 5 mg to about 60 mg of hydrocodone or a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

each multiparticulate individually coated with a coating consisting of (i) ethylcellulose, (ii) a wax and (iii) optional plasticizer(s),

said dosage form, after a first administration to a human patient, provides a C₁₂/C_max hydrocodone ratio of 0.55 to 0.85 and a therapeutic effect for about 12 hours.

2. The dosage form of claim 1, which provides a C₁₂/C_max hydrocodone ratio of 0.65 to 0.75.

3. The dosage form of claim 1, which provides an in-vitro release of from 18% to about 42.5% by weight of hydrocodone from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37°

C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37°

C.

4. The dosage form of claim 1, which provides a dissolution rate in-vitro of hydrocodone from the dosage form when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 1.2 at 37°

C. from about 25 to about 65% by weight hydrocodone released after 2 hours, from about 45 to about 85% by weight hydrocodone released after 4 hours, and greater than about 60% by weight hydrocodone released after 8 hours.

5. The dosage form of claim 1, which provides a dissolution rate in-vitro of hydrocodone from the dosage form when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 7.5 at 37°

C. from about 25 to about 65% by weight hydrocodone released after 2 hours, from about 45 to about 85% by weight hydrocodone released after 4 hours, and greater than about 60% by weight hydrocodone released after 8 hours.

6. The dosage form of claim 1, which provides a T_max of hydrocodone in said patient at from about 2 to about 8 hours after oral administration of the dosage form.

7. The dosage form of claim 1, which provides a T_max of hydrocodone in said patient at from about 4 to about 6 hours after oral administration of the dosage form.

8. The dosage form of claim 1, which provides a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after administration and provides a plasma concentration of hydrocodone of at least 6 ng/ml at about 12 hours after administration, based on oral administration of a dosage form containing 15 mg hydrocodone bitartrate.

9. The dosage form of claim 8, which provides a plasma concentration of hydrocodone of at least 8 ng/ml at from about 3 to about 7 hours after administration.

10. The dosage form of claim 1, which maintains a plasma concentration of hydrocodone within 80% of C_max for about 4 to about 8 hours during the 12 hour dosing interval.

11. The dosage form of claim 1, which maintains a plasma concentration of hydrocodone within 90% of C_max for about 2 to about 5 hours during the 12 hour dosing interval.

12. The dosage form of claim 1, wherein the wax is glyceryl behenate.

13. The dosage form of claim 1, wherein each multiparticulate is in the form of a matrix bead.

22. The dosage form of claim 1, wherein the human patient is a fasted human patient.

14. A solid oral controlled-release dosage form, the dosage form comprising a compressed tablet comprising

a plurality of multiparticulates collectively consisting essentially of from about 5 mg to about 60 mg of the hydrocodone or an equivalent amount of the pharmaceutically acceptable salt thereof, ethylcellulose and hydroxypropylmethyl cellulose,

each multiparticulate individually coated with a coating consisting of (i) ethylcellulose, (ii) a wax and (iii) optional plasticizer(s),

the multiparticulates interdispersed along with an additional amount of hydroxypropylmethyl cellulose and lactose in the compressed tablet,

said dosage form, after a first administration to a patient population, provides a mean C₁₂/C_max hydrocodone ratio of 0.55 to 0.85 and a therapeutic effect for about 12 hours.

15. The dosage form of claim 14, which provides an in-vitro release of from 18% to about 42.5% by weight of hydrocodone from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37°

C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37°

C.

16. The dosage form of claim 14, which provides a mean C₁₂/C_max hydrocodone ratio of 0.65 to 0.75.

17. The dosage form of claim 14, wherein each multiparticulate is in the form of a matrix bead.

23. The dosage form of claim 14, wherein the patient population is a fasted patient population.

18. A solid oral twice-a-day controlled-release dosage form, the dosage form comprising

a plurality of individually coated multiparticulates collectively consisting of an amount of hydrocodone bitartrate equivalent to from about 5 mg to about 60 mg hydrocodone, ethylcellulose, hydroxypropylmethyl cellulose, a wax and optional plasticizer(s),

each multiparticulate is a matrix bead consisting of hydrocodone bitartrate, hydroxypropylmethyl cellulose and ethylcellulose, and

individually coated with a coating consisting of (i) ethylcellulose, (ii) a wax and (iii) optional plasticizer(s),

the individually coated multiparticulates compressed with an additional amount of hydroxypropylmethyl cellulose, lactose and a metal stearate into a tablet,

said dosage form, after a first administration to a human patient population, provides a mean C₁₂/C_max hydrocodone ratio of 0.55 to 0.85 and a therapeutic effect for about 12 hours.

19. The dosage form of claim 18, which provides a mean C₁₂/C_max hydrocodone ratio of 0.65 to 0.75.

20. The dosage form of claim 18, which provides an in-vitro release of from 18% to about 42.5% by weight of hydrocodone from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37°

C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37°

C.

21. The dosage form of claim 18, wherein the individually coated multiparticulates are compressed with the additional amount of hydroxypropylmethyl cellulose, lactose, the metal stearate, and a colorant into the tablet.

24. The dosage form of claim 18, wherein the patient population is a fasted patient population.