Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans

• US 20110287095A1
• Filed: 06/22/2011
• Published: 11/24/2011
• Est. Priority Date: 12/22/2009
• Status: Active Grant

• Current Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Gupta, Vishal K., Dhanarajan, Anish, Overholt, Stephen, Park, Jae Han, Eisenhauer, Tiffani
• Granted Patent: US 8,597,681 B2
• Time in Patent Office: Days
• US Class Current: 424/457
• 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 method for the preparation of a solid dosage form pharmaceutical composition comprising a morphinan and at least one other active pharmaceutical ingredient, the method comprising:

(a) granulating a mixture comprising the morphinan and at least one excipient in a manner such that the amount of morphinan exposed on the surface of the granule is substantially reduced thereby forming a morphinan-protected granule;

(b) granulating a mixture comprising the morphinan-protected granule, the active pharmaceutical agent, and at least one excipient to form a granulated mixture; and

(c) blending the granulated mixture with a release-controlling polymer comprising a polyethylene oxide polymer to form the solid dosage form pharmaceutical composition comprising a sustained release layer.

2. The method of claim 1, wherein the active pharmaceutical agent is acetaminophen.

3. The method of claim 1, wherein the morphinan comprises up to about 90% of the total weight of the morphinan-protected granule formed in step (a).

4. The method of claim 1, wherein the morphinan is chosen from adulmine, allocryptopine, aporphine, benzylmorphine, berberine, bicuculine, bicucine, bulbocapnine, buprenorphine, butorphanol, canadine, capaurine, chelerythrine, chelidonine, codamine, codeine, coptisine, coreximine, corlumine, corybulbine, corycavamine, corycavine, corydaline, corydine, corytuberine, cularine, cotamine, cryptopine, cycloartenol, cycloartenone, cyclolaudenol, dehydroreticuline, desomorphine, dextropropoxyphene, dextrorphanol, diacetylmorphine, dicentrine, dihydrosanguinarine, dipropanoylmorphine, epiporphyroxine, ethylmorphine, eupaverine, fagarine, fentanyl, glaucine, homochelidonoine, hydrocodone, hydrocotarnine, hydromorphone, hydroxythebaine, isoboldine, isocorybulbine, isocorydine, isocorypalmine, isoquinoline, laudanidine, laudanine, laudanosine, levorphanol, magnoflorine, meconic acid, methadone, morphine, nalbuphine, nalmefene, naloxone, naltrexamine, α

-naltrexol, β

-naltrexol, naltrexone, naphthaphenanthridine, narceine, narceinone, narcotoline, narcotine, neopine, nicomorphine, norlaudanosoline, norsanguinarine, noscapine, opium, oripavine, oxycodone, oxymorphone, oxysanguinarine, palaudine, papaverine, papaveraldine, papaverrubine, perparin, pethidine, phenanthrene, phtalide-isoquinoline, porphyroxine, protopine, pseudocodeine, pseudomorphine, reticuline, salutaridine, sinoacutine, sanguinarine, scoulerine, somniferine, stepholidine, tapentadol, tetrahydroprotoberberine, thebaine, tramadol, and xanthaline.

5. The method of claim 1, wherein the d₉₀ of the morphinan is less than the d₉₀ of the excipient in the morphinan-protected granule, or the d₉₀ of the morphinan is less than about 80% of the d₉₀ of the excipient in the morphinan-protected granule.

6. The method of claim 1, wherein less than about 90% of the morphinan is exposed on the surface of the morphinan-protected granules.

7. The method of claim 1, wherein the morphinan-protected granules have a d₉₀ of less than about 2000 micrometers.

8. The method of claim 1, wherein the granulation in step (a) and (b) is done using a device chosen from a low-shear wet granulator, a high-shear wet granulator, a fluid-bed granulator, a roller compactor, a vertical granulator, an oscillating granulator, a gelatinizer, a pelletizer, a spheronizer, and combinations thereof.

9. The method of claim 1, wherein the excipient in step (a) or (b) is chosen from a filler, an antioxidant, a pH-adjusting agent, a chelating agent, an antimicrobial agent, a release-controlling polymer, and combinations of any of the foregoing excipients.

10. The method of claim 1, wherein the morphinan-protected granule from step (a) is granulated with the active pharmaceutical agent and at least one excipient to form an immediate release layer.

11. The method of claim 1, wherein the morphinan is substantially resistant to oxidative degradation.

12. The method of claim 1, wherein the solid dosage form pharmaceutical composition is chosen from granules, uncoated tablets, coated tablets, mini-tablets, bilayer tablets, orally disintegrating tablets, hard capsules, and multilayer capsules.

13. The method of claim 1, wherein the morphinan is hydrocodone and the active pharmaceutical agent is acetaminophen.

14. A method for the preparation of a solid dosage form pharmaceutical composition comprising oxycodone and acetaminophen, the method comprising:

(a) granulating a mixture comprising the oxycodone and at least one excipient in a manner such that the amount of oxycodone exposed on the surface of the granule is substantially reduced thereby forming an oxycodone-protected granule;

(b) granulating a mixture comprising the oxycodone-protected granule, the acetaminophen, and at least one excipient to form a granulated mixture; and

(c) blending the granulated mixture with a release-controlling polymer comprising a polyethylene oxide polymer to form the solid dosage form pharmaceutical composition comprising a sustained release layer.

15. The method of claim 14, wherein the oxycodone comprises up to about 90% of the total weight of the oxycodone-protected granule formed in step (a).

16. The method of claim 14, wherein the d₉₀ of the oxycodone is less than the d₉₀ of the excipient in the oxycodone-protected granule, or the d₉₀ of the oxycodone is less than about 80% of the d₉₀ of the excipient in the oxycodone-protected granule.

17. The method of claim 14, wherein less than about 90% of the oxycodone is exposed on the surface of the oxycodone-protected granules.

18. The method of claim 14, wherein the oxycodone-protected granules have a d₉₀ of less than about 2000 micrometers.

19. The method of claim 14, wherein the granulation in step (a) and (b) is done using a device chosen from a low-shear wet granulator, a high-shear wet granulator, a fluid-bed granulator, a roller compactor, a vertical granulator, an oscillating granulator, a gelatinizer, a pelletizer, a spheronizer, and combinations thereof.

20. The method of claim 14, wherein the excipient in step (a) or (b) is chosen from a filler, an antioxidant, a pH-adjusting agent, a chelating agent, an antimicrobial agent, a release-controlling polymer, and combinations of any of the foregoing excipients.

21. The method of claim 14, wherein the oxycodone-protected granule from step (a) is granulated with the acetaminophen and at least one excipient to form an immediate release layer.

22. The method of claim 14, wherein the oxycodone is substantially resistant to oxidative degradation.

23. The method of claim 14, wherein the solid dosage form pharmaceutical composition contains less than about 0.5% w/w 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.

24. The method of claim 14, wherein the solid dosage form pharmaceutical composition contains less than about 0.5% w/w of each of any one or more degradants 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.

25. The method of claim 14, wherein the solid dosage form pharmaceutical composition is chosen from granules, uncoated tablets, coated tablets, mini-tablets, mini-tablets, bilayer tablets, orally disintegrating tablets, hard capsules, and multilayer capsules.

26. The method of claim 21, wherein the solid dosage form pharmaceutical composition is a bilayer tablet.

27. The method of claim 26, wherein the excipients in the sustained release layer comprise at least one antioxidant, binder, diluent, and glidant, and the excipients in the immediate release layer comprise binder, glidant, disintegrant, and lubricant.

28. A method for the preparation of a bilayer tablet comprising a sustained release layer and an immediate release layer, the method comprising:

(a) granulating a mixture comprising oxycodone or hydrocodone and at least one excipient in a manner such that the amount of oxycodone or hydrocodone exposed on the surface of granule is substantially reduced thereby forming a morphinan-protected granule;

(b) granulating a mixture comprising the morphinan-protected granule of step (a), the acetaminophen, and at least one excipient to form a granulated mixture;

(c) blending the granulated mixture with a release-controlling polymer comprising a polyethylene oxide polymer to form the sustained release layer; and

(d) granulating a mixture comprising the morphinan-protected granule of step (a), the acetaminophen, and at least one excipient to form the immediate release layer.

29. A granule substantially resistant to oxidative degradation of oxycodone, the granule comprising an interior region substantially comprising oxycodone that is surrounded by an exterior region substantially comprising at least one excipient, wherein the granule contains less than about 0.5% w/w of the total mass of oxycodone 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.

30. The granule of claim 29, 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 the 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.

31. The granule of claim 29, wherein less than about 90% of the oxycodone is exposed on the surface of the granule.

32. The granule of claim 29, wherein the oxycodone comprises from about 10% to about 60% of the total weight of the granule.

33. The granule of claim 29, wherein the excipient is chosen from binders, fillers, antioxidants, pH adjusting agents, chelating agents, antimicrobial agents, and combinations thereof.

34. The granule of claim 29, wherein the excipient comprises microcrystalline cellulose, pregelatinized starch, Na₂EDTA, citric acid, and combinations thereof.

35. The granule of claim 29, wherein the oxycodone is (+)-oxycodone, (−

)-oxycodone, and combinations thereof.

36. The granule of claim 29, wherein the oxycodone has a d₉₀ that is less than the d₉₀ of the excipient.

37. The granule of claim 36, wherein the d₉₀ of the oxycodone is less than about 80% of the d₉₀ of the excipient.

38. The granule of claim 29, wherein the granule comprises at least one other pharmaceutically active agent in addition to oxycodone.

39. A granule substantially resistant to oxidative degradation of hydrocodone, the granule comprising an interior region substantially comprising hydrocodone that is surrounded by an exterior region substantially comprising at least one excipient, wherein the granule contains less than about 0.5% w/w of the total mass of hydrocodone 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.

40. 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 in a manner such that the amount of morphinan exposed on the surface of the granule is substantially reduced thereby forming the morphinan-protected granule.

41. The granule of claim 40, wherein the morphinan is oxycodone.

42. The granule of claim 40, wherein the morphinan is hydrocodone.

43. 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 that is surrounded by an exterior region substantially comprising at least one excipient, wherein the granule contains less than about 0.5% w/w of the total mass of oxycodone 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.

44. 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 an interior region substantially comprising hydrocodone that is surrounded by an exterior region substantially comprising at least one excipient, wherein the granule contains less than about 0.5% w/w of the total mass of hydrocodone 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.

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

(a) granulating a mixture comprising the oxycodone and at least one excipient in a manner such that the amount of oxycodone exposed on the surface of the granule is substantially reduced thereby forming the plurality of oxycodone-protected granules;

(b) granulating a mixture comprising the plurality of oxycodone-protected granules, the acetaminophen, and at least one excipient to form a granulated mixture; and

(c) blending the granulated mixture with a release-controlling polymer comprising a polyethylene oxide polymer to form the solid dosage form the pharmaceutical composition comprising a sustained release layer.