Controlled release hydrocodone formulations

• US 9,056,107 B1
• Filed: 03/02/2015
• Issued: 06/16/2015
• 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
• Application Number:
  US14/635,198
• Publication Number:
  US 20150174121A1
• Time in Patent Office: 106 Days
• US Class Current: 1/1
• 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 comprising a pharmaceutically acceptable capsule or tablet comprising:

multiparticulates comprising (i) a material selected from the group consisting of gums, alkylcelluloses, acrylic polymers, waxes, shellac, oils and mixtures thereof, and (ii) a pharmaceutically acceptable salt of hydrocodone selected from the group consisting of bitartrate salts of hydrocodone, hydrocodone hydrochloride, hydrocodone p-toluenesulfonate, hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodone sulfate, hydrocodone trifluoroacetate, hydrocodone hemipentahydrate, hydrocodone pentafluoropropionate, hydrocodone p-nitrophenylhydrazone, hydrocodone o-methyloxime, hydrocodone semicarbazone, hydrocodone hydrobromide, hydrocodone mucate, hydrocodone oleate, hydrocodone phosphate dibasic, hydrocodone phosphate monobasic, hydrocodone acetate trihydrate, hydrocodone bis(heptafuorobutyrate), hydrocodone bis(methylcarbamate), hydrocodone bis(pentafluoropropionate), hydrocodone bis(pyridine carboxylate), hydrocodone bis(trifluoroacetate), hydrocodone chlorhydrate, and hydrocodone sulfate pentahydrate,

wherein at least some of the multiparticulates are coated with a coating comprising an alkylcellulose, an acrylic polymer, or a mixture thereof,

the total amount of the pharmaceutically acceptable salt of hydrocodone in the dosage form is equivalent to from about 0.5 mg to about 1250 mg of hydrocodone, and

the dosage form after a first administration to a human provides

a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after administration and 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,

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

a therapeutic effect for at least about 12 hours.

2. The dosage form of claim 1, wherein the coating comprises an acrylic polymer comprising a methyl methacrylate copolymer.

3. The dosage form of claim 1, wherein the pharmaceutically acceptable salt of hydrocodone is hydrocodone bitartrate, and the dosage form comprises from about 5 mg to about 60 mg of hydrocodone bitartrate.

4. The dosage form of claim 1, wherein the material is selected from the group consisting of gums, alkylcelluloses, waxes, and mixtures thereof, and the dosage form provides a therapeutic effect for about 12 hours.

5. The dosage form of claim 1, wherein the material is a wax.

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

7. 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.

8. The dosage form of claim 1, which provides an in-vitro release 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. such that from about 25% to about 65% by weight hydrocodone is released after 2 hours, from about 45% to about 85% by weight hydrocodone is released after 4 hours, and greater than about 60% by weight hydrocodone is released after 8 hours.

9. The dosage form of claim 7, which is a twice-a-day dosage form.

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

11. The dosage form of claim 1, wherein the multiparticulates are in the form of matrix beads.

12. The dosage form of claim 1, which is a capsule.

13. The dosage form of claim 1, which is a tablet.

14. 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.

15. A solid oral controlled-release dosage form comprising a pharmaceutically acceptable capsule or tablet comprising:

multiparticulates comprising (i) a material selected from the group consisting of gums, alkylcelluloses, acrylic polymers, waxes, shellac, oils and mixtures thereof and (ii) a pharmaceutically acceptable salt of hydrocodone selected from the group consisting of inorganic salts of hydrocodone and bitartrate salts of hydrocodone,

wherein the total amount of the pharmaceutically acceptable salt of hydrocodone in the dosage form is equivalent to from about 0.5 mg to about 1250 mg of hydrocodone, and

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

a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after administration and 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,

a mean T_max of hydrocodone at from about 2 to about 8 hours,

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

a therapeutic effect for at least about 12 hours.

29. The dosage form of claim 15, wherein at least some of the multiparticulates are coated with a coating comprising an acrylic polymer or an alkylcellulose, and the dosage form provides a therapeutic effect for about 12 hours.

30. The dosage form of claim 15, wherein the material is a wax.

16. A solid oral controlled-release dosage form comprising a capsule or tablet comprising:

multiparticulates comprising (i) a material selected from the group consisting of gums, alkylcelluloses, acrylic polymers, waxes, shellac, oils and mixtures thereof and (ii) a pharmaceutically acceptable salt of hydrocodone selected from the group consisting of inorganic salts of hydrocodone and bitartrate salts of hydrocodone thereof,

wherein the total amount of the pharmaceutically acceptable salt of hydrocodone in the dosage form is equivalent to from about 0.5 mg to about 1250 mg of hydrocodone, and

the dosage form provides

a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after administration and 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, and

an in-vitro release of hydrocodone from the dosage form when measured by the USP Paddle or basket method at 100 rpm in 900 ml aqueous buffer at a pH of 7.5 at 37°

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

17. The dosage form of claim 16, wherein the multiparticulates are in the form of matrix beads.

18. The dosage form of claim 17, wherein at least some of the matrix beads are coated with a coating comprising an acrylic polymer or an alkylcellulose.

19. The dosage form of claim 16, wherein the material is a wax.

20. The dosage form of claim 16, which is a capsule comprising from about 5 mg to about 60 mg of hydrocodone bitartrate.

21. A solid oral controlled-release oral dosage form comprising

a pharmaceutically acceptable salt of hydrocodone selected from the group consisting of inorganic salts of hydrocodone and bitartrate salts of hydrocodone, wherein

the dosage form is a pharmaceutically acceptable capsule comprising matrix multiparticulates comprising up to 80% (by weight) of an aliphatic alcohol having from 8 to 20 carbon atoms,

the dosage form providing after a first administration to a human

a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after administration and 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,

a C₁₂/C_max hydrocodone ratio of 0.55 to 0.85,

a T_max of hydrocodone at from about 2 to about 8 hours, and

a therapeutic effect such that it may be administered about every 12 hours.

22. The dosage form of claim 21, wherein the aliphatic alcohol is a fatty acid, and the dosage form comprises a bitartrate salt of hydrocodone.

23. The dosage form of claim 22, wherein the fatty acid is selected from the group consisting of cetyl alcohol, cetostearyl alcohol and stearyl alcohol.

24. The dosage form of claim 21, wherein the dosage form is a capsule comprising from about 5 mg to about 60 mg of hydrocodone bitartrate.

25. The dosage form of claim 21, 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.

26. The dosage form of claim 21, wherein a portion of the pharmaceutically acceptable salt of hydrocodone is in an immediate release form, and the remaining portion of the pharmaceutically acceptable salt of hydrocodone is in a controlled release form.

27. The dosage form of claim 21, wherein the pharmaceutically acceptable salt of hydrocodone is hydrocodone bitartrate.

28. The dosage form of claim 21, wherein the matrix multiparticulates comprise a wax.