Methods of manufacturing oral dosage forms

• US 10,076,516 B2
• Filed: 12/13/2016
• Issued: 09/18/2018
• Est. Priority Date: 10/29/1999
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Oshlack, Benjamin, Huang, Hua-Pin, Masselink, John, Tonelli, Alfred
• Primary Examiner(s): Basquill, Sean M
• Application Number:
  US15/376,868
• Publication Number:
  US 20170136006A1
• Time in Patent Office: 644 Days
• 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 process for the preparation of a solid oral dosage form comprising:

compressing a therapeutically effective amount of hydrocodone and one or more excipients into a tablet such that the tablet releases hydrocodone at such a rate that plasma concentrations of hydrocodone are maintained within the therapeutic range but below toxic concentrations for about 12 hours or longer, and

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

a hydrocodone plasma concentration of at least 5 ng/ml at 12 hours after administration.

2. The process of claim 1, wherein the dosage form provides controlled release of hydrocodone for about 12 hours.

3. The process of claim 1, wherein the dosage form provides controlled release of hydrocodone for about 24 hours.

4. The process of claim 3, wherein the dosage form provides a hydrocodone plasma concentration of at least about 8 ng/ml at about 2 hours after administration.

5. The process of claim of claim 4, wherein one of the excipients is a pharmaceutically acceptable polymer.

6. The process of claim 5, wherein the pharmaceutically acceptable polymer comprises between 1% and 80% of the tablet by weight.

7. The process of claim 1, wherein one of the excipients is a material having a melting point of from 30 to about 200°

C.

8. The process of claim 5, wherein the pharmaceutically acceptable polymer is a hydroxyalkylcellulose.

9. The process of claim 8, wherein the hydroxyalkylcellulose is a hydroxypropylcellulose or a hydroxypropylmethylcellulose.

10. The process of claim 9, wherein the hydroxyalkylcellulose is the hydroxypropylmethylcellulose.

11. The process of claim 7, wherein the material is a polyalkylene glycol.

12. The process of claim 1, wherein the dosage form provides a C_max that increases linearly from one dosage strength to another.

13. The process of claim 3, wherein the dosage form provides a plasma concentration profile of hydrocodone with a C₁₂/C_max hydrocodone ratio of 0.55 to 0.85.

14. The process of claim 3, wherein the dosage form provides a plasma concentration profile of hydrocodone with a C₁₂/C_max hydrocodone ratio of 0.55 to 0.65.

15. The process of claim 3, wherein the dosage form provides a plasma concentration profile of hydrocodone with a C₁₂/C_max hydrocodone ratio of 0.65 to 0.85.

16. The process of claim 14, wherein said C₁₂/C_max hydrocodone ratio is calculated from hydrocodone plasma concentrations from first administration of the dosage form to a population of fasted humans.

17. The process of claim 15, wherein said C₁₂/C_max hydrocodone ratio is calculated from hydrocodone plasma concentrations from first administration of the dosage form to a population of fasted humans.

18. The process of claim 14, wherein a portion of the plasma concentration profile of hydrocodone is relatively flat.

19. The process of claim 14, wherein said C₁₂/C_max hydrocodone ratio is calculated from hydrocodone plasma concentrations from first administration of the dosage form to a fed human.

20. The process of claim 15, wherein said C₁₂/C_max hydrocodone ratio is calculated from hydrocodone plasma concentrations from first administration of the dosage form to a fed human.

21. The process of claim 13, wherein said C₁₂/C_max hydrocodone ratio is calculated from hydrocodone plasma concentrations from first administration of the dosage form to a population of fed humans.

22. The process of claim 1, wherein said hydrocodone plasma concentrations are hydrocodone plasma concentrations from first administration of the dosage form to a fasted human.

23. The process of claim 1, wherein said hydrocodone plasma concentrations are hydrocodone plasma concentrations from first administration of the dosage form to a fed human.

24. A process for the preparation of a solid oral dosage form comprising:

formulating a tablet comprising from about 5 mg to about 1250 mg of hydrocodone and one or more excipients such that the tablet provides

a controlled release of hydrocodone over about 8 to about 24 hours,

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

a hydrocodone plasma concentration of at least 5 ng/ml at 12 hours after administration.

25. The process of claim 24, wherein the tablet comprises a bitartrate salt of hydrocodone.

26. The process of claim 24, wherein the dosage form provides a hydrocodone plasma concentration of at least about 8 ng/ml at about 2 hours after administration.

27. The process of claim 24, wherein the dosage form provides a plasma concentration profile of hydrocodone with a C₁₂/C_max hydrocodone ratio of 0.55 to 0.85.

28. The process of claim 27, wherein a portion of the plasma concentration profile of hydrocodone is relatively flat.

29. The process of claim 27, wherein said C₁₂/C_max hydrocodone ratio is calculated from hydrocodone plasma concentrations from first administration of the dosage form to a fasted human.

30. The process of claim 24, wherein said hydrocodone plasma concentrations are hydrocodone plasma concentrations from first administration of the dosage form to a fed human.

31. A process for the preparation of a solid oral dosage form comprising:

compressing a therapeutically effective amount of hydrocodone and one or more excipients into a tablet such that the tablet

releases hydrocodone at such a rate that plasma concentrations of hydrocodone are maintained within the therapeutic range but below toxic concentrations for about 12 hours or longer and

provides a hydrocodone plasma concentration of at least 6 ng/ml at about 12 hours after first administration, a hydrocodone plasma concentration of at least about 8 ng/ml at about 8 hours after administration, and a C₁₂/C_max hydrocodone ratio of 0.55 to 0.85.

32. A process for the preparation of a solid oral dosage form comprising:

formulating a tablet comprising from about 5 mg to about 1250 mg of hydrocodone and one or more excipients such that the tablet provides

a controlled release of hydrocodone over about 8 to about 24 hours,

a hydrocodone plasma concentration of at least 6 ng/ml at about 12 hours after first administration,

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

a C₁₂/C_max hydrocodone ratio of 0.55 to 0.85.