Methods of manufacturing oral formulations

• US 10,022,368 B2
• Filed: 12/13/2016
• Issued: 07/17/2018
• Est. Priority Date: 10/30/2000
• 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 K, Tonelli, Alfred
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US15/376,774
• Publication Number:
  US 20170151229A1
• Time in Patent Office: 581 Days
• 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 process for the preparation of a solid oral formulation comprising:

formulating a tablet comprising a bitartrate salt of hydrocodone and a pharmaceutically acceptable polymer, the pharmaceutically acceptable polymer comprising between 1% and 80% of the formulation by weight,

wherein the tablet is coated with a coating that excludes semipermeable polymers, the bitartrate salt of hydrocodone is the only drug in the tablet, and the formulation provides an in-vitro release rate of hydrocodone, 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 1hour, 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.

2. The process of claim 1, wherein the tablet is a molded tablet.

3. The process of claim 1, wherein the pharmaceutically acceptable polymer is polyethylene oxide.

4. The process of claim 3, wherein the formulation further comprises a hydroxyalkylcellulose.

5. The process of claim 4, wherein the hydroxyalkylcellulose is a hydroxypropylcellulose or a hydroxypropylmethylcellulose.

6. The process of claim 5, wherein the tablet is formulated such that it maintains plasma concentrations of hydrocodone within the therapeutic range over 12 hours or longer after administration and is administrable on a once a day basis.

7. The process of claim 1, wherein the tablet is formulated such that it provides therapeutically effective plasma concentrations of hydrocodone for about 24 hours after oral administration.

8. The process of claim 7, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration of the formulation to a human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 1.0.

9. The process of claim 7, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration of the formulation to a human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 0.85.

10. The process of claim 7, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone comprising a portion that is relatively flat.

11. The process of claim 7, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration of the formulation to a human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 0.7.

12. The process of claim 7, wherein the tablet is formulated such that it provides plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration of the formulation to the human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 0.6.

13. The process of claim 8, wherein the ratio is calculated from hydrocodone plasma concentration from first administration of the formulation to the human.

14. The process of claim 12, wherein the ratio is calculated from hydrocodone plasma concentration from first administration of the formulation to the human.

15. A process for the preparation of a solid oral formulation comprising:

compressing a bitartrate salt of hydrocodone and a pharmaceutically acceptable polymer into a tablet, the pharmaceutically acceptable polymer comprising between 1% and 80% of the tablet by weight, wherein

the tablet is coated with a coating that excludes semipermeable polymers,

the bitartrate salt of hydrocodone is the only drug in the tablet, and

the tablet provides an in-vitro release rate of hydrocodone, 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.

16. The process of claim 15, wherein the tablet is formulated such that it maintain plasma concentrations of hydrocodone within the therapeutic range over 12 hours or longer after administration to a human.

17. The process of claim 15, wherein the tablet is formulated such that it provides a C_max of hydrocodone that increases linearly from one dosage strength to another.

18. The process of claim 15, wherein the tablet is formulated such that it provides an AUC of hydrocodone that increases linearly from one dosage strength to another.

19. The process of claim 15, wherein the pharmaceutically acceptable polymer is polyethylene oxide.

20. The process of claim 16, wherein the tablet further comprises a hydroxyalkylcellulose.

21. The process of claim 20, wherein the hydroxyalkylcellulose is a hydroxypropylcellulose or a hydroxypropylmethylcellulose.

22. The process of claim 15, wherein the tablet is formulated such that it maintains therapeutically effective plasma concentrations of hydrocodone for about 24 hours after oral administration to a human.

23. The process of claim 22, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration to the human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 1.0.

24. The process of claim 22, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration to the human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 0.85.

25. The process of claim 22, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone comprising a portion that is relatively flat.

26. The process of claim 22, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration to the human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 0.7.

27. The process of claim 23, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration to the human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 0.6.

28. The process of claim 24, wherein the ratio is calculated from hydrocodone plasma concentration from first administration of the tablet to the human.

29. The process of claim 27, wherein the ratio is calculated from hydrocodone plasma concentration from first administration of the tablet to the human.

30. A process for the preparation of a solid oral formulation comprising:

formulating a tablet comprising a bitartrate salt of hydrocodone and a material having a melting point of from about 30 to about 200°

C., the material comprising between 1% and 80% of the tablet by weight, wherein the tablet is coated with a coating that excludes semipermeable polymers, the bitartrate salt of hydrocodone is the only drug in the tablet, and

the tablet provides an in-vitro release rate of hydrocodone, 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.

31. The process of claim 30, wherein the melting point is from about 30 to about 100°

C.

32. The process of claim 31, wherein the melting point is from about 45 to about 90°

C.

33. The process of claim 32, wherein the material is polyethylene oxide.

34. The process of claim 33, wherein the tablet further comprises a hydroxyalkylcellulose.

35. The process of claim 34, wherein the hydroxyalkylcellulose is hydroxypropylcellulose.

36. The process of claim 30, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration to the human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 1.0.

37. The process of claim 30, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration to the human to the highest concentration of hydrocodone during the 24 hours of from 0.55 to 0.85.

38. The process of claim 30, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone comprising a portion that is relatively flat.

39. The process of claim 37, wherein the tablet is formulated such that it provides a plasma concentration profile of hydrocodone with a ratio of the plasma concentration of hydrocodone at 24 hours after oral administration to the human to the highest concentration of hydrocodone during the 24 hours of 0.55 to 0.6.

40. The process of claim 36, wherein the ratio is calculated from hydrocodone plasma concentration from first administration of the tablet to the human.