Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans

• US 8,597,681 B2
• Filed: 06/22/2011
• Issued: 12/03/2013
• Est. Priority Date: 12/22/2009
• Status: Expired due to Fees

• Current Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Original Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Inventors: Park, Jae Han, Eisenhauer, Tiffani, Dhanarajan, Anish, Gupta, Vishal K., Overholt, Stephen
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Cohen, Michael P
• Application Number:
  US13/166,770
• Publication Number:
  US 20110287095A1
• Time in Patent Office: 895 Days
• Field of Search: None
• US Class Current: 424/472
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• 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 9/2081 with microcapsules or coated microparticles according to A61K9/50
• 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: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Abstract

Methods for producing stabilized solid dosage form pharmaceutical compositions are provided. In particular, methods for preparing protected granules containing morphinans, and solid dosage form pharmaceutical compositions produced using the morphinan-protected granules are provided.

Claims

1. A granule substantially resistant to oxidative degradation of oxycodone, the granule comprising an interior region substantially comprising oxycodone and an exterior region substantially comprising at least one excipient selected from the group consisting of a binder, a filler, an antioxidant, a chelating agent, and combinations thereof, wherein the exterior region surrounds the interior region, and wherein the granule contains less than about 0.5% w/w of the total mass of oxycodone of each of any one or more of a degradant selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide after being stored for 6 months at 40°

C. and 75% relative humidity.

2. The granule of claim 1, wherein less than about 20% of the total weight of the oxycodone in the granule is exposed on the surface of the granule.

3. The granule of claim 1, further comprising at least one additional excipient selected from the group consisting of pH adjusting agents, antimicrobial agents, and combinations thereof.

4. The granule of claim 1, wherein the granule comprises microcrystalline cellulose, pregelatinized starch, Na₂EDTA, and citric acid.

5. The granule of claim 1, wherein the oxycodone has a d₉₀ that is less than the d₉₀ of the excipient.

6. The granule of claim 5, wherein the d₉₀ of the oxycodone is less than about 80% of the d₉₀ of the excipient.

7. The granule of claim 1, wherein the oxycodone is oxycodone hydrochloride.

8. The granule of claim 1, further comprising at least one additional active pharmaceutical ingredient.

9. The granule of claim 8, wherein the at least one additional active pharmaceutical ingredient comprises acetaminophen.

10. The granule of claim 1, further comprising a hydrophilic polymer.

11. The granule of claim 10, wherein the hydrophilic polymer is selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabicgum, carrageensgum, ghaftigum, guargum, karayagum, locust beangurn, okragum, tragacanthgum, scleroglucangum, xanthangum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride propylene or copolymers of maleic anhydride isobutylene), crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, diesters of polyglucan, polyacrylamides, polyacrylic acid, polyamides, polyethylene glycols, polyethylene oxides, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof.

12. The granule of claim 1, further comprising a hydrophobic polymer.

13. The granule of claim 12, wherein the hydrophobic polymer is selected from the group consisting of cellulose acetate butyrate, cellulose acetate ethylcarbamate, cellulose acetate heptanoate, cellulose acetate methylcarbamate, cellulose acetate octanoate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate trimaletate, cellulose acetaldehyde dimethyl acetate, cellulose butyrate, cellulose dimethylaminoacetate, cellulose disuccinate, cellulose dipalmitate, cellulose dicaprylate, cellulose propionate, cellulose propionate succinate, cellulose trioctanoate, cellulose tripropionate, cellulose trimellitate, cellulose tripalmitate, cellulose trivalerate, cellulose valerate palmitate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, ethylhydroxy ethylcellulose, hydroxy propyl methylcellulose phthalate, methyl cellulose, methyl ethyl cellulose, propyl cellulose, sodium carboxymethyl starch, polyvinyl acetate phthalate, polyvinyl alcohol phthalate, methacrylic acid copolymers, methacrylic acid ester copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylate), poly(methacrylate), poly(methyl methacrylate), poly(ethylacrylate), poly(ethyl methacrylate), poly(methacrylic acid anhydride), glycidyl methacrylate copolymers, ammonio methacrylate copolymers, lecithins, aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated castor oil, hydrogenated vegetable oil, 12-hydroxystearyl alcohol, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristyl alcohol, stearic acid, stearyl alcohol, polyethyleneglycols, zein, shellac, bee'"'"'s wax, carnauba wax, glyceryl behenate, Japan wax, paraffin, spermaceti, synthetic waxes, and combinations thereof.

14. A granule substantially resistant to oxidative degradation of hydrocodone, the granule comprising hydrocodone, and at least one excipient chosen from a binder, a filler, an antioxidant, a chelating agent, and combinations thereof, wherein the granule contains less than about 0.5% w/w of the total mass of hydrocodone of each of any one or more of a degradant selected from hydrocodone-n-oxide and hydrocodone aldol dimer after being stored for 6 months at 40°

C. and 75% relative humidity.

15. A granule substantially resistant to oxidative degradation of a morphinan, the granule prepared by a process comprising granulating a mixture comprising the morphinan and at least one excipient chosen from a binder, a filler, an antioxidant, a chelating agent, and combinations thereof in a manner such that substantially all of the morphinan is surrounded by the at least one excipient, thereby forming the morphinan-protected granule;

when the morphanin is oxycodone, the granule contains less than about 0.5% w/w of the total mass of oxycodone of one or more of a degradant selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide, after being stored for 6 months at 40°

C. and 75% relative humidity, and when the morphanin is hydrocodone, the granule contains less than about 0.5% w/w of the total mass of hydrocodone of each of one or more of a degradant selected from hydrocodone-n-oxide and hydrocodone aldol dimer, after being stored for 6 months at 40°

C. and 75% relative humidity.

16. The granule of claim 15, wherein the morphinan is oxycodone.

17. The granule of claim 16, wherein the granule contains less than about 0.5% w/w of the total mass of oxycodone of each of any one or more of a degradant selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide thereof after being stored for 6 months at 40°

C. and 75% relative humidity.

18. The granule of claim 15, wherein the morphinan is hydrocodone.

19. The granule of claim 15, wherein the granule comprises microcrystalline cellulose, pregelatinized starch, Na₂EDTA, and citric acid.

20. A pharmaceutical composition comprising a plurality of oxycodone-containing granules substantially resistant to oxidative degradation of oxycodone and at least one pharmaceutically acceptable carrier, the plurality of granules comprising an interior region substantially comprising oxycodone and an exterior region substantially comprising at least one excipient, wherein the pharmaceutical composition contains less than about 0.5% w/w of the total mass of oxycodone of each of any one or more of a degradant selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide after being stored for 6 months at 40°

C. and 75% relative humidity.

21. The pharmaceutical composition of claim 20, wherein less than about 30% of the total weight of the oxycodone in the oxycodone-containing granules is exposed on the surface of the granules.

22. The pharmaceutical composition of claim 20, wherein the at least one pharmaceutically acceptable carrier is incompatible with oxycodone.

23. The pharmaceutical composition of claim 22, wherein the at least one pharmaceutically acceptable carrier is a polyethylene oxide polymer.

24. The pharmaceutical composition of claim 20, further comprising at least one additional active pharmaceutical ingredient.

25. The pharmaceutical composition of claim 24, wherein the at least one additional active pharmaceutical ingredient comprises acetaminophen.

26. The pharmaceutical composition of claim 25, further comprising a plurality of tablet granules comprising the oxycodone-containing granules, the acetaminophen, and at least one additional excipient.

27. The pharmaceutical composition of claim 26, wherein the at least one additional excipient is a polyethylene oxide polymer.

28. The pharmaceutical composition of claim 26, wherein the at least one pharmaceutically acceptable carrier is a polyethylene oxide polymer.

29. A pharmaceutical composition comprising a plurality of hydrocodone-containing granules substantially resistant to oxidative degradation of hydrocodone and at least one pharmaceutically acceptable carrier, the plurality of granules comprising hydrocodone and at least one excipient, wherein the pharmaceutical composition contains less than about 0.5% w/w of the total mass of hydrocodone of each of any one or more of a degradant selected from hydrocodone-n-oxide and hydrocodone aldol dimer after being stored for 6 months at 40°

C. and 75% relative humidity.

30. The pharmaceutical composition of claim 29, wherein the hydrocodone-protected granules have a physical structure that reduces the amount of hydrocodone exposed on the surface of the granules.

31. The pharmaceutical composition of claim 29, wherein the pharmaceutically acceptable carrier is incompatible with hydrocodone.

32. The pharmaceutical composition of claim 29, further comprising at least one additional active pharmaceutical ingredient.

33. A solid dosage pharmaceutical composition comprising a plurality of oxycodone-protected granules and acetaminophen, the composition prepared by a process comprising:

(a) granulating a first mixture comprising the oxycodone and at least one excipient to form the plurality of oxycodone-protected granules, wherein the oxycodone in the oxycodone-protected granules is substantially resistant to oxidative degradation;

(b) granulating a second mixture in the presence of a granulation fluid, the second mixture comprising the plurality of oxycodone-protected granules, the acetaminophen, and at least one additional excipient to form a plurality of tablet granules; and

(c) blending the plurality of tablet granules with a release-controlling polymer comprising a polyethylene oxide polymer and optionally at least one carrier to form the solid dosage pharmaceutical composition comprising a sustained release layer;

wherein the granule contains less than about 0.5% w/w of the total mass of oxycodone of one or more of a degradant selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide, after being stored for 6 months at 40°

C. and 75% relative humidity.

34. The solid dosage pharmaceutical composition of claim 33, further comprising step (d) which includes granulating a third mixture in the presence of a granulation fluid, the third mixture comprising oxycodone-protected granules, acetaminophen, and at least one additional excipient to form a plurality of immediate release granules, and step (e) blending the immediate release granules with at least one excipient to form an immediate release layer.

35. The pharmaceutical composition of claim 33, wherein less than about 30% of the total weight of the oxycodone in the tablet granules is exposed on the surface of the granules.

36. A granule prepared by a process comprising:

(a) granulating a first mixture comprising oxycodone and at least one excipient to form a first granulated mixture;

(b) granulating a second mixture in the presence of a granulation fluid, the second mixture comprising the first granulated mixture, acetaminophen, and at least one additional excipient to form a second granulated mixture;

wherein the first granulated mixture and the second granulated mixture comprise the granule; and

wherein the granule contains less than about 0.5% w/w of the total mass of oxycodone of each of any one or more of a degradant selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide after being stored for 6 months at 40°

C. and 75% relative humidity.

37. The granule of claim 36, further comprising blending the granule with a release-controlling polymer.

38. The granule of claim 37, wherein the release-controlling polymer is a polyethylene oxide polymer

39. The granule of claim 36, further comprising blending the granule with a lubricant.