Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans

• US 20130273153A1
• Filed: 06/22/2011
• Published: 10/17/2013
• Est. Priority Date: 12/22/2009
• Status: Active Grant

• Current Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Park, Jae Han, Eisenhauer, Tiffani, Dhanarajan, Anish, Gupta, Vishal K., Overholt, Stephen
• Granted Patent: US 9,198,861 B2
• Time in Patent Office: Days
• US Class Current: 424/452
• 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 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/485 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 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/209 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 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209

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 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 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, hydrocotamine, 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.

10. A granule substantially resistant to oxidative degradation of a morphinan selected from the group consisting of oxycodone and hydrocodone the granule comprising an interior region substantially comprising the morphinan and an exterior region substantially comprising at least one excipient chosen from 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 a degradant after being stored for 6 months at 40°

C. and 75% relative humidity.

11. The granule of claim 10, wherein less than about 20% of the total weight of the morphinan in the granule is exposed on the surface of the granule.

12. The granule of claim 10, further comprising at least one additional active pharmaceutical ingredient.

13. The granule of claim 12, wherein the at least one additional active pharmaceutical ingredient is acetaminophen.

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

(a) granulating a first mixture comprising the morphinan and at least one excipient to form the 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, 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 and optionally at least one carrier to form the solid dosage pharmaceutical composition comprising a sustained release layer.

15. The solid dosage pharmaceutical composition of claim 14, further comprising step (d) which includes granulating a third mixture in the presence of a granulation fluid, the third mixture comprising morphinan-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.

16. The solid dosage pharmaceutical composition of claim 14, wherein less than about 30% of the total weight of the morphinan in the tablet-protected granules is exposed on the surface of the granules.

17. The solid dosage pharmaceutical composition of claim 14, wherein the at least one pharmaceutically acceptable carrier is incompatible with the morphinan.

18. The solid dosage pharmaceutical composition of claim 14, wherein the morphinan is oxycodone and the degradant is selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide.

19. The solid dosage pharmaceutical composition of claim 14, wherein the morphinan is hydrocodone and the degradant is selected from hydrocodone-n-oxide and hydrocodone aldol dimer.

20. The solid dosage pharmaceutical composition of claim 14, wherein the release-controlling polymer is a hydrophilic polymer.

21. The solid dosage pharmaceutical composition of claim 14, wherein the hydrophilic polymer is a polyethylene oxide.