Controlled release hydrocodone formulations

• US 8,980,291 B2
• Filed: 12/30/2010
• Issued: 03/17/2015
• 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): Haghighatian, Mina
• Assistant Examiner(s): KARPINSKI, LUKE E
• Application Number:
  US12/982,386
• Publication Number:
  US 20110262532A1
• Time in Patent Office: 1,538 Days
• Field of Search: None
• US Class Current: 424/401
• 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 twice-a-day controlled-release dosage form, wherein

the dosage form is a tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices collectively consisting of from about 5 mg to about 60 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) hydroxypropylmethyl cellulose,

(iii) lactose,

(iv) a metal stearate, and

(v) a colorant,

the individually coated multiparticulates compressed along with hydroxypropylmethyl cellulose, lactose, the metal stearate and the colorant into the tablet,

said dosage form, after a first administration to a human patient, provides

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

a C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for at least 12 hours,

wherein the hydrocodone or pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

2. The dosage form of claim 1, wherein said matrices are in the form of unextruded granules.

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

4. The dosage form of claim 1, which provides an in-vitro release of from 18% to about 42.5% by weight of the hydrocodone or pharmaceutically acceptable salt thereof 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.

5. The dosage form of claim 3, which provides an in-vitro release of from 18% to about 42.5% by weight of the hydrocodone or pharmaceutically acceptable salt thereof 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.

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

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

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

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

8. 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 said administration.

9. The dosage form of claim 1, which provides a T_max of hydrocodone in said patient at from about 3 to about 7 hours after said administration.

10. 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 said administration.

11. The dosage form of claim 1, which provides a plasma concentration of hydrocodone of at least 8 ng/ml at from about 3 to about 7 hours after said administration.

12. The dosage form of claim 1, which provides a time to 80% mean C_max of hydrocodone from about 0.5 to about 1.5 hours after first administration to a patient population.

13. The dosage form of claim 1, which provides a time to 90% mean C_max of hydrocodone of from about 1.5 to about 2.5 hours after first administration to a patient population.

14. The dosage form of claim 1, which provides a time to 90% mean C_max of hydrocodone of from about 1.8 to about 2.2 hours after first administration to a patient population.

15. The dosage form of claim 1, which maintains a plasma concentration of hydrocodone within 80% of C_max of hydrocodone for about 1 to about 9 hours during the 12 hour dosing interval.

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

17. The dosage form of claim 1, which maintains a plasma concentration of hydrocodone within 90% of C_max of hydrocodone for about 1 to about 6.5 hours during the 12 hour dosing interval.

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

19. The dosage form of claim 1, which provides a mean in-vivo absorption rate of hydrocodone from administration to T_max of from about 1.5 mg/hour to about 5 mg/hour and provides a mean rate of absorption from T_max to the end of the dosing interval which is less than 0.5 mg/hour, based on a first oral administration of a dosage form containing 15 mg hydrocodone bitartrate to a patient population.

20. The dosage form of claim 19, which provides a mean in-vivo absorption rate of hydrocodone from administration to T_max of from about 2 mg/hour to about 4 mg/hour.

21. The dosage form of claim 19, which provides a mean in-vivo absorption rate of hydrocodone from T_max to the end of the 12 hour dosing interval which is from about 0.08 mg/hour to about 0.4 mg/hour.

23. The dosage form of claim 1, wherein the pharmaceutically acceptable salt is a bitartrate salt.

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

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

22. A solid oral twice-a-day controlled-release dosage form, wherein

the dosage form is a tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices collectively consisting of from about 5 mg to about 60 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) hydroxypropylmethyl cellulose,

(iii) lactose,

(iv) a metal stearate, and

(v) a colorant,

the individually coated multiparticulates compressed along with hydroxypropylmethyl cellulose, lactose, the metal stearate and the colorant into the tablet,

said dosage form, after a first administration to a patient population, provides

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

a mean C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for about 12 hours,

wherein the hydrocodone or the pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

24. The dosage form of claim 22, wherein said matrices are in the form of unextruded granules.

29. The dosage form of claim 22, wherein the patient population is a fasted patient population.

25. A solid oral twice-a-day controlled-release dosage form, wherein the dosage form is a tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices consisting of hydrocodone or a pharmaceutically acceptable salt thereof, ethylcellulose, hydroxypropylmethyl cellulose and glyceryl behanate,

(ii) hydroxypropylmethyl cellulose,

(iii) lactose,

(iv) a metal stearate, and

(v) a colorant,

the individually coated multiparticulates compressed along with hydroxypropylmethyl cellulose, lactose, the metal stearate, and the colorant into the tablet,

said dosage form, after a first administration to a human patient, provides

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

a C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for at least 12 hours,

wherein the hydrocodone or pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

26. The dosage form of claim 25, wherein the wax is glyceryl behenate.

30. The dosage form of claim 25, wherein the human patient is a fasted human patient.

31. A solid oral twice-a-day controlled-release dosage form, wherein the dosage form is a tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices consisting of hydrocodone or a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) an additional amount of hydrocodone or pharmaceutically acceptable salt thereof,

(iii) hydroxypropylmethyl cellulose,

(iv) lactose,

(v) a metal stearate, and

(vi) a colorant,

the individually coated multiparticulates compressed along with the additional amount of hydrocodone or pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose, lactose, the metal stearate and colorant into the tablet,

said dosage form, after a first administration to a human patient, provides

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

a C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for at least 12 hours,

wherein the hydrocodone or pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the amount of the hydrocodone in the dosage form is from about 5 mg to about 60 mg,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

32. A solid oral twice-a-day controlled-release dosage form, wherein the dosage form is a tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices collectively consisting of hydrocodone or a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) an additional amount of hydrocodone or pharmaceutically acceptable salt thereof,

(iii) hydroxypropylmethyl cellulose,

(iv) lactose,

(v) a metal stearate, and

(vi) a colorant,

the individually coated multiparticulates compressed along with the additional amount of hydrocodone or pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose, lactose, the metal stearate and the colorant into the tablet,

said dosage form, after a first administration to a patient population, provides

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

a mean C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for about 12 hours,

wherein the hydrocodone or the pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the amount of the hydrocodone in the dosage form is from about 5 mg to about 60 mg,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

33. A solid oral twice-a-day controlled-release dosage form, the dosage form is a film coated tablet, the tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices consisting of hydrocodone or a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) an additional amount of hydrocodone or pharmaceutically acceptable salt thereof,

(iii) hydroxypropylmethyl cellulose,

(iv) lactose,

(v) a metal stearate, and

(vi) a colorant,

the individually coated multiparticulates compressed along with the additional amount of hydrocodone or pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose, lactose, the metal stearate and the colorant into the tablet, the tablet coated with the film,

said dosage form, after a first administration to a human patient, provides

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

a C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for at least 12 hours,

wherein the hydrocodone or pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the amount of the hydrocodone in the dosage form is from about 5 mg to about 60 mg,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

34. A solid oral twice-a-day controlled-release dosage form, wherein the dosage form is a film coated tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices collectively consisting of hydrocodone or a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) an additional amount of hydrocodone or pharmaceutically acceptable salt thereof,

(iii) hydroxypropylmethyl cellulose,

(iv) lactose,

(v) a metal stearate, and

(vi) a colorant,

the individually coated multiparticulates compressed along with the additional amount of hydrocodone or pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose, lactose, the metal stearate and the colorant into a tablet, the tablet coated with the film,

said dosage form, after a first administration to a patient population, provides

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

a mean C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for about 12 hours, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the amount of the hydrocodone in the dosage form is from about 5 mg to about 60 mg,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

35. A solid oral twice-a-day controlled-release dosage form, wherein the dosage form is a film coated tablet, the tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices collectively consisting of from about 5 mg to about 60 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) hydroxypropylmethyl cellulose,

(iii) lactose,

(iv) a metal stearate, and

(v) a colorant,

the individually coated multiparticulates compressed along with hydroxypropylmethyl cellulose, lactose, the metal stearate and the colorant into the tablet, the tablet coated with the film,

said dosage form, after a first administration to a human patient, provides

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

a C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for at least 12 hours,

wherein the hydrocodone or pharmaceutically acceptable salt thereof is the only active agent in the dosage form,

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.

36. A solid oral twice-a-day controlled-release dosage form, wherein the the dosage form is a film coated tablet, the tablet consisting of

(i) a plurality of individually coated multiparticulates consisting of matrices individually coated with a coating consisting of ethylcellulose and a wax, the matrices collectively consisting of from about 5 mg to about 60 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose and ethylcellulose,

(ii) hydroxypropylmethyl cellulose,

(iii) lactose,

(iv) a metal stearate, and

(v) a colorant,

the individually coated multiparticulates compressed along with hydroxypropylmethyl cellulose, lactose, the metal stearate and the colorant into the tablet, the tablet coated with the film,

said dosage form, after a first administration to a patient population, provides

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

a mean C₁₂/C_max ratio of 0.55 to 0.85, and

a therapeutic effect for about 12 hours, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is the only active agent in the dosage form, and

the metal stearate is magnesium stearate, and

the wax is selected from the group consisting of beeswax, glycowax, castor wax, carnauba wax, and glyceryl behenate.