Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
View Patent ↗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.
1. A granule substantially resistant to oxidative degradation of hydrocodone, the granule comprising an interior region substantially comprising the hydrocodone 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 hydrocodone 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.
2. The granule of claim 1 , wherein less than about 20% of the total weight of the hydrocodone in the granule is exposed on the surface of the granule.
3. The granule of claim 1 , further comprising at least one additional active pharmaceutical ingredient.
4. The granule of claim 2 , wherein the at least one additional active pharmaceutical ingredient is acetaminophen.
5. A solid dosage pharmaceutical composition comprising a plurality of hydrocodone protected granules and acetaminophen, the composition prepared by a process comprising:
(a) granulating a first mixture comprising the hydrocodone and at least one excipient to form the plurality of hydrocodone protected granules, wherein the hydrocodone in the hydrocodone protected granules is substantially resistant to oxidative degradation and wherein the granule contains less than about 0.5% w/w of the total mass of hydrocodone 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;
(b) granulating a second mixture in the presence of a granulation fluid, the second mixture comprising the plurality of hydrocodone 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 pharmaceutically acceptable carrier to form the solid dosage pharmaceutical composition comprising a sustained release layer.
6. The solid dosage pharmaceutical composition of claim 5 , further comprising step (d) which includes granulating a third mixture in the presence of a granulation fluid, the third mixture comprising hydrocodone 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.
7. The solid dosage pharmaceutical composition of claim 5 , wherein less than about 30% of the total weight of the hydrocodone in the protected granules is exposed on the surface of the granules.
8. The solid dosage pharmaceutical composition of claim 5 , wherein the at least one pharmaceutically acceptable carrier is incompatible with the hydrocodone.
9. The solid dosage pharmaceutical composition of claim 5 , wherein the release-controlling polymer is a hydrophilic polymer.
10. The solid dosage pharmaceutical composition of claim 9 , wherein the hydrophilic polymer is a polyethylene oxide.