Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans

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

(a) granulating a first mixture comprising the morphinan and at least one excipient to form a plurality of morphinan-protected granules, wherein the morphinan in the morphinan 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 morphinan-protected granules, acetaminophen, and at least one 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 excipient to form the solid dosage form pharmaceutical composition comprising a sustained release layer.

2 . The method of claim 1 , wherein the morphinan is chosen from adlumine, 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, cotarnine, 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.

3 . 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.

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

5 . 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.

6 . The method of claim 1 , wherein the method further comprises (d) granulating a third mixture comprising the plurality of morphinan-protected granules, the acetaminophen, and at least one excipient to form a plurality of immediate release granules.

7 . The method of claim 6 wherein the method further comprises:

(e) blending the immediate release granules with at least one excipient to form the immediate release layer.

8 . The method of claim 1 , wherein the morphinan is hydrocodone.

9 . The method of claim 1 , wherein the morphinan is oxycodone.