Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans

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.

What is claimed is: 
     
         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.